Use of endothelin receptor antogonists for the treatment of tumour diseases

ABSTRACT

Use of endothelin receptor antagonists for the preparation of a medicament for the treatment of tumour diseases.

The invention relates to the use of endothelin receptor antagonistsselected from the group consisting of

-   -   a) the compounds of the formula I described in EP 0733626        in which    -   -A=B—C=D- is a —CH═CH—CH═CH— group in which 1 or 2 CH has (have)        been replaced by N,    -   Ar is Ph or naphthyl, each of which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by H, Hal, A,        alkenyl having up to 6 carbon atoms, Ph, OPh, NO₂, NR⁴R⁵,        NHCOR⁴, CF₃, OCF₃, CN, OR⁴, COOR⁴, (CH₂)_(n)COOR⁴,        (CH₂)_(n)NR⁴R⁵, —N═C═O or NHCONR⁴R⁵,    -   R¹, R²    -   and R³ are each, independently of one another, absent, H, Hal,        A, CF₃, NO₂, NR⁴R⁵, CN, COOR⁴ or NHCOR⁴,    -   R⁴ and R⁵ are each, independently of one another, H or A, or        together are alternatively —CH₂—(CH₂)_(n)—CH₂—,    -   A is alkyl having from 1 to 6 carbon atoms,    -   Ph is phenyl,    -   X is O or S,    -   Hal is F, Cl, Br or I,    -   n is 1, 2 or 3,    -   and salts thereof;    -   b) the compounds of the formula I described in EP 0758650        in which    -   X is a saturated, fully unsaturated or partially unsaturated 3-        to 4-membered alkylene chain, in which from 1 to 3 carbon atoms        may be replaced by N and/or 1 or 2 carbon atoms may be replaced        by 1-2 O atoms and/or 1-2 S atoms, but where at most up to 3        carbon atoms are replaced and where, in addition, a        monosubstitution, disubstitution or trisubstitution of the        alkylene chain and/or of a nitrogen located therein by A, R⁸        and/or NR⁴R^(4′) may occur, and where, furthermore, one CH₂        group in the alkylene chain may also be replaced by a C═O group,    -   A is alkyl having 1-6 carbon atoms, in which one or two CH₂        groups may be replaced by O or S atoms or by —CR⁴═CR^(4′)—        groups and in addition 1-7 H atoms may be replaced by F,    -   R¹ is H or A,    -   R² is COOR⁴, CN, 1H-tetrazol-5-yl or CONHSO₂R⁸,    -   R³ is Ar,    -   R⁴ and R^(4′) are each, independently of one another, H, alkyl        having from 1 to 6 carbon atoms or benzyl,    -   Ar is phenyl or naphthyl, each of which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by R⁵, R⁶ or        R⁷, or a        group which is unsubstituted or monosubstituted or disubstituted        in the phenyl moiety by R⁵ or R⁶,    -   R⁵, R ⁶    -   and R⁷ are each, independently of one another, R⁴, OR⁴, Hal,        CF₃, OCF₃, OCHF₂, OCH₂F, NO₂, NR⁴R^(4′), NHCOR⁴, CN, NHSO₂R⁴        COOR⁴, COR⁴, CONHSO₂R⁸, O(CH₂)_(n)R², OPh, O(CH₂)_(n)OR⁴ or        S(O)_(m)R⁴,    -   R⁸ is phenyl or naphthyl, each of which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by A, OR¹,        NR⁴R^(4′) or Hal,    -   E is CH₂ or O,    -   D is carbonyl or [C(R⁴R^(4′))]_(n),    -   Hal is F, Cl, Br or I,    -   m is 0, 1 or 2,    -   n is1 or 2,    -   and salts thereof;    -   c) the compounds of the formula I described in EP 0755934        in which    -   —Y-Z- is —NR⁷—CO—, —N═C(OR⁷)— or —N═CR⁸—,    -   R¹ is Ar,    -   R² is COOR⁶, CN, 1H-tetrazol-5-yl or CONHSO₂Ar,    -   R³, R⁴    -   and R⁵ are each, independently of one another, R⁶, OR⁶,        S(O)_(m)R⁶, Hal, NO₂, NR⁶R^(6′), NHCOR⁶, NHSO₂R⁶, OCOR⁶, COOR⁶        or CN,    -   R⁶ and R^(6′) are each, independently of one another, H, alkyl        having from 1 to 6 carbon atoms, benzyl or phenyl,    -   R⁷ is (CH₂)_(n)Ar,    -   R⁸ is Ar or OAr,    -   Ar is phenyl which is unsubstituted or monosubstituted,        disubstituted or trisubstituted by R⁹, R¹⁰ or R¹¹, or        unsubstituted naphthyl, or a        group which is unsubstituted or monosubstituted or disubstituted        in the phenyl moiety by R⁹ or R¹⁰, or a        group which is unsubstituted or monosubstituted or disubstituted        in the cyclohexadienyl moiety by R⁹ or R¹⁰,    -   R⁹, R¹⁰    -   and R¹¹ are each, independently of one another, R⁶, OR⁶, Hal,        CF₃, OCF₃, OCHF₂, OCH₂F, NO₂, NR⁶R^(6′), NHCOR⁶, CN, NHSO₂R⁶,        COOR⁶, COR⁶, CONHSO₂Ar, O(CH₂)_(n)R², O(CH₂)_(n)OR⁶ or        S(O)_(m)R⁶,    -   E is CH₂, S or O,    -   D is carbonyl or [C(R⁶R^(6′))]_(n),    -   Hal is F, Cl, Br or I,    -   X is O or S,    -   m is0, 1 or 2,    -   n is 1 or 2,    -   and salts thereof;    -   d) the compounds of the formula I described in EP 0757039        in which    -   —Y-Z- is —NR⁷—CO—, —N═C(OR— or —N═CR⁸—,    -   R¹ is Ar,    -   R² is COOR⁶, (CH₂)_(n)COOR , CN, 1H-tetrazol-5-yl or CONHSO₂Ar,    -   R³, R⁴    -   and R⁵ are each, independently of one another, R⁶, OR⁶,        S(O)_(m)R⁶, Hal, NO₂, NR⁶R^(6′), NHCOR⁶, NHSO₂R⁶, OCOR⁶, COR⁶,        COOR6 or CN, where R³ and R⁴ together can alternatively be an        O(CH₂)_(n)O group,    -   R⁶ and R^(6′) are each, independently of one another, H, alkyl        having from 1 to 6 carbon atoms, benzyl or phenyl,    -   R⁷ is (CH₂)_(n)Ar,    -   R⁸ is Ar or OAr,    -   Ar is phenyl which is unsubstituted or monosubstituted,        disubstituted or trisubstituted by R⁹, R¹⁰ or R¹¹, or        unsubstituted naphthyl, or a        group which is unsubstituted or monosubstituted or disubstituted        in the phenyl moiety by R⁹ or R¹⁰, or a        group which is unsubstituted or monosubstituted or disubstituted        in the cyclohexadienyl moiety by R⁹ or R¹⁰,    -   R⁹, R¹⁰    -   and R¹¹ are each, independently of one another, R⁶, OR⁶, Hal,        CF₃, OCF₃, OCHF₂, OCH₂F, NO₂, NR⁶R^(6′), NHCOR⁶, CN, NHSO₂R⁶,        COOR⁶, COR⁶, CONHSO₂Ar, O(CH₂)_(n)R², O(CH₂)_(n)OR⁶ or        S(O)_(m)R⁶,    -   E is CH₂, S or O,    -   D is carbonyl or [C(R⁶R^(6′))]_(n),    -   X is O or S,    -   Hal is F, Cl, Br or I,    -   m is0, 1 or 2,    -   n is 1, 2or 3,    -   and salts thereof;    -   e) the compounds of the formula I described in EP 0796250        in which    -   Y is —C(R⁴R^(4′))—C(R⁴R^(4′))—, —CR⁴═CR^(4′)— or        —C(R⁴R^(4′))—S—,    -   R¹ is Het, Ar, R³ or R⁴,    -   R² is Ar or        -   a            group which is unsubstituted or monosubstituted or            disubstituted in the phenyl moiety by A, R³, OR⁴, NH₂, NHA,            NA₂, NO₂, CN, Hal, NHCOR⁴, NHSO₂R⁴, COOR⁴, COR⁴, CONHSO₂R⁶,            O(CH₂)_(n)R³, OPh, O(CH₂)_(n)OR⁴ or S(O)_(m)R⁴, or a            group which is unsubstituted or monosubstituted or            disubstituted in the cyclohexadienyl moiety by A, R³, OR⁴,            NH₂, NHA, NA₂, NO₂, CN, Hal, NHCOR⁴, NHSO₂R⁴, COOR⁴, COR⁴,            CONHSO₂R⁶, O(CH₂)_(n)R³, OPh, O(CH₂)_(n)OR⁴ or S(O)_(m)R⁴,    -   R³ is CN, COOH, COOA, CONHSO₂R⁵ or 1H-tetrazol-5-yl,    -   R⁴ and R^(4′) are each, independently of one another, H, A, or        phenyl or benzyl, each of which is unsubstituted or        monosubstituted by alkoxy,    -   R⁵ is A or Ar,    -   R⁶ is phenyl or naphthyl, each of which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by A, OR⁵, NH₂,        NHA, NA₂, NO₂, CN or Hal,    -   A is alkyl having 1-6 carbon atoms, in which one or two CH₂        groups may be replaced by O or S atoms or by —CR⁴═CR^(4,)—        groups and in addition 1-7 H atoms may be replaced by F,        -   or benzyl,    -   Ar is phenyl or naphthyl, each of which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by A, OR⁴, NH₂,        NHA, NA₂, NO₂, CN, Hal, NHCOR⁴, NHSO₂R⁴, COOR⁴, COR⁴, CONHSO₂R⁶,        O(CH₂)_(n)R³, OPh, O(CH₂)_(n)OR⁴ or S(O)_(m)R⁴,    -   Het is a monocyclic or bicyclic saturated, unsaturated or        aromatic heterocyclic radical having from 1 to 4 N, O and/or S        atoms, bonded via N or C, which may be unsubstituted or        monosubstituted, disubstituted or trisubstituted by Hal, A, R³,        NH₂, NHA, NA₂, CN, NO₂ and/or carbonyl oxygen,    -   D is carbonyl or [C(R⁴R^(4′))]_(n),    -   E is CH₂, S or O,    -   Hal is F, Cl, Br or I,    -   X is O or S,    -   m is 0, 1 or 2,    -   n is 1 or 2,    -   and salts thereof;    -   f) the compounds of the formula I described in WO 9719077        in which    -   R is    -   X is O or S,    -   R¹ is H, Hal, OH, OA, A, alkylene-O-A, NO₂, NH₂, NH-acyl,        SO₂NH₂, SO₃-A, SO₂NHA, CN or formyl,    -   R² is H or A,    -   R³, R⁵, R⁶,    -   R⁷ and R⁸ are each, independently of one another, H, Hal, OH,        OA, O-alkylene-R⁴, A, S-A, NO₂, NH₂, NHA, NA₂, NH-acyl, NHSO₂A,        NHSO₂R⁴, NASO₂A, NASO₂—R⁴, NH(CO)NH₂, NH(CO)NHA, formyl,        NH(CO)NH-phenyl, NHCOOA, NA-acyl, NHR⁴, NHCOOR⁴, NHCOO-benzyl,        NHSO₂-benzyl, NHCOO-alkylene-OA, NH(CO)NA₂, N-piperidinyl-CO—NH,        N-pyrrolidinyl-CONH, O(CH₂)_(n)COOR², O(CH₂)_(n)OR², CH₂OH or        CH₂OA,    -   R³ and R⁶ together are alternatively —O—CH₂—O—, —O—CH₂—CH₂—O—,        —O—CH₂—CH₂—, —O—CF₂—O— or —O—CF₂—CF₂—O—,    -   R⁴ is phenyl which is unsubstituted or monosubstituted or        polysubstituted by R³ and/or R⁶,    -   A is alkyl having 1-6 carbon atoms,    -   Hal is fluorine, chlorine, bromine or iodine,    -   n is 1 or 2,    -   and salts thereof;    -   g) the compounds of the formula I described in WO 9730982        in which    -   R is    -   X is O or S,    -   R¹ is H, Hal, OH, OA, A, alkylene-O-A, NO₂, NH₂, NH-acyl,        SO₂NH₂, SO₃-A, SO₂NHA, CN or formyl,    -   R², R³    -   and R⁴ are each, independently of one another, a phenyl group        which is unsubstituted or monosubstituted or polysubstituted by        Hal, OH, OA, O-alkylene-R⁵, A, S-A, SOA, SO₂A, SOR⁵, SO₂R⁵, NO₂,        NH₂, NHA, NA₂, NH-acyl, NHSO₂A, NHSO₂R⁵, NASO₂A, NASO₂—R⁵,        NH(CO)NH₂, NH(CO)NHA, formyl, NH(CO)NHR⁵, NHCOOA, NA-acyl,        NHCOOCH₂R⁵, NHSO₂CH₂R⁵, NHCOO-alkylene-OA, NH(CO)NA₂, 1        -piperidinyl-CO—NH, 1-pyrrolidinyl-CONH, O(CH₂)_(n)COOA,        O(CH₂)_(n)COOH, O(CH₂)_(n)OH, O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH,        COOA, CH₂COOH or CH₂COOA,        -   a            group or a            group, where R² is additionally A or cycloalkyl,    -   R⁵ is a phenyl group which is unsubstituted or monosubstituted        or polysubstituted by Hal, OH, OA, A, S-A, NO₂, NH₂, NHA, NA₂,        NH-acyl, NHSO₂A, NASO₂A, NH(CO)NH₂, NH(CO)NHA, formyl, NHCOOA,        NA-acyl, NHCOO-alkylene-OA, NH(CO)NA₂, N-piperidinyl-CO—NH,        N-pyrrolidinyl-CONH, O(CH₂)_(n)COOA, O(CH₂)_(n)COOH,        O(CH₂)_(n)OH, O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH, COOA, CH₂COOH or        CH₂COOA,    -   A is alkyl having 1-6 carbon atoms, in which one or two CH₂        groups may be replaced by O or S atoms or by —CR⁶═CR^(6′)—        groups and/or 1-7 H atoms may be replaced by F,    -   D is carbonyl or [C(R⁶R^(6′))]_(m),    -   E is CH₂, S or O,    -   Y is O or S,    -   R⁶ and R^(6′) are each, independently of one another, H, F or A,    -   Hal is fluorine, chlorine, bromine or iodine,    -   n is 1 or 2, and    -   m is 1 or 2,    -   or a tautomeric cyclised form, and the (E)-isomers and the salts        of all isomers;    -   h) the compounds of the formula I described in WO 9730996        in which    -   -A=B—C=D- is a —CH═CH—CH═CH— group, in which, in addition, 1 or        2 CH may be replaced by N,    -   Het is a monocyclic or bicyclic saturated, unsaturated or        aromatic heterocyclic radical having from 1 to 4 N, O and/or S        atoms which is unsubstituted or substituted by -Z-R⁶,    -   R¹, R²    -   and R³ are each, independently of one another, absent, H, Hal,        A, CF₃, NO₂, NR⁴R⁵, CN, COOR⁴ or NHCOR⁴,    -   R⁴ and R⁵ are each, independently of one another, H or A, or        together are alternatively —CH₂—(CH₂)_(n)—CH₂—,    -   R⁶ is a phenyl radical, a benzothiadiazol-5-yl radical or a        benzoxadiazol-5-yl radical, each of which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by R⁷, R⁸        and/or R⁹,    -   R⁷, R⁸    -   and R⁹ are each, independently of one another, A, O-A, CN, COOH,        COOA, Hal, formyl or —CO-A, and R⁷ and R⁸ together are        alternatively —O—(CH₂)_(m)—O—,    -   A is alkyl having from 1 to 6 carbon atoms,    -   X is O or S,    -   Z is —CO—, —CONH—, —CO—(CH₂)_(n)—, —CH═CH—, —(CH₂)_(n)—,        —CONHCO—, —NHCONH—, —NHCOO—, —O—CONH—, —CO—O— or —O—CO—,    -   Hal is F, Cl, Br or I,    -   m is 1 or 2, and    -   n is1, 2 or 3,    -   and salts thereof;    -   i) the compounds of the formula I described in DE 19609597        in which    -   Ar is naphthyl which is monosubstituted by NH₂, NHA or NA₂, and    -   A is alkyl having from 1 to 6 carbon atoms,    -   and physiologically acceptable salts thereof;    -   j) the compounds of the formula I described in DE 19612101        in which    -   —Y-Z- is —NR⁴—CO or —N═CR⁵—,    -   R¹ is Ar,    -   R² is H, alkyl having 1-6 carbon atoms which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by OR³ or Hal,        or (CH₂)_(m)Ph or (CH₂)_(m)-cycloalkyl, each of which is        unsubstituted or monosubstituted, disubstituted or        trisubstituted by R³, OR³ or Hal,    -   R³ and R^(3′) are each, independently of one another, H, alkyl        having 1-6 carbon atoms or benzyl,    -   R⁴ is CH₂Ar,    -   R⁵ is OCH₂Ar,    -   Ar is phenyl which is unsubstituted or monosubstituted,        disubstituted or trisubstituted by R⁶, R⁷ or R⁸, or a        group which is unsubstituted or monosubstituted in the phenyl        moiety by R⁶, or a        group which is unsubstituted or monosubstituted in the        cyclo-hexadienyl moiety by R⁶,    -   E is CH₂ or O,    -   D is carbonyl or (CH₂)_(n),    -   E and D together are alternatively CH═CR⁹,    -   R⁶ and R^(6′) are each, independently of one another, R³, OR³ or        Hal,    -   R⁷ is R³, OR³, Hal, NO₂, NH₂, NHR³, NR³R^(3′), NHCOR³, COOR³,        O(CH₂)_(n)R³ or O(CH₂)_(n)OR³,    -   R⁸ is Ph which is unsubstituted or monosubstituted,        disubstituted or trisubstituted by R³, OR³, Hal, NO₂, NH₂, NHR⁶,        NR⁶R^(6′), NHCOR³ or COOR³,    -   R⁹ is H, OH, CH₂OH or COOR³,    -   Hal is F, Cl, Br or I,    -   Ph is phenyl,    -   m is 0 or 1,    -   n is 1 or 2,    -   and salts thereof;    -   k) the compounds of the formula I described in WO 9827091        in which    -   R is phenyl which is unsubstituted or monosubstituted,        disubstituted or trisubstituted by R³, R⁴ or R⁵ or is        2,1,3-benzothiadiazolyl which is unsubstituted or        monosubstituted by R²,    -   R¹ is A, in which 1-7 H atoms may be replaced by F, or is —S-A        or —O-A, or phenyl or -alkylene-phenyl, each of which is        unsubstituted or monosubstituted by R³, or thienyl which is        unsubstituted or monosubstituted by R³,    -   R² is A, F, Cl, Br or —O-A,    -   R³, R⁴    -   and R⁵ are each, independently of one another, A, —O-A, —S-A,        —O-alkylene-COOH, -alkylene-COOH or COOH,    -   R³ and R⁴ together are alternatively —O—CH₂—O—, and    -   A is alkyl having 1-7 carbon atoms,    -   and salts thereof;    -   I) the compounds of the formula I described in WO 9827077        in which    -   R is    -   X is O or S,    -   R¹ is H, Hal, OH, OA, A, alkylene-O-A, NO₂, NH₂, NH-acyl,        SO₂NH₂, SO₃-A, SO₂NHA, CN or formyl,    -   R², R³    -   and R⁴ are each, independently of one another, a phenyl group        which is unsubstituted or monosubstituted or polysubstituted by        R⁷, where R² is additionally A or cycloalkyl,        -   a            group or a            group, with the proviso that at least one of the radicals            R², R³ or R⁴ is an R⁸ radical which is unsubstituted or            mono-substituted or polysubstituted by R⁷,    -   R⁵ is a phenyl group which is unsubstituted or monosubstituted        or polysubstituted by Hal, OH, OA, A, S-A, NO₂, NH₂, NHA, NA₂,        NH-acyl, NHSO₂A, NASO₂A, NH(CO)NH₂, NH(CO)NHA, formyl, NHCOOA,        NA-acyl, NHCOO-alkylene-OA, NH(CO)NA₂, N-piperidinyl-CO—NH,        N-pyrrolidinyl-CONH, O(CH₂)_(n)COOA, O(CH₂)_(n)COOH,        O(CH₂)_(n)OH, O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH, COOA, CH₂COOH or        CH₂COOA,    -   A is alkyl having 1-6 carbon atoms, in which one or two CH₂        groups may be replaced by O or S atoms or by —CR⁶═CR^(6′)—        groups and/or 1-7 H atoms may be replaced by F,    -   D is carbonyl or [C(R⁶R^(6′))]_(m),    -   E is CH₂, S or O,    -   Y is O or S,    -   R⁶ and R^(6′) are each, independently of one another, H, F or A,    -   R⁷ is Hal, OH, OA, O-alkylene-R⁵, A, S-A, S—OA, SO₂A, S—OR⁵,        SO₂R⁵, NO₂, NH₂, NHA, NA₂, NH-acyl, NHSO₂A, NHSO₂R⁵, NASO₂A,        NASO₂,R⁵, NH(CO)NH₂, NH(CO)NHA, formyl, NH(CO)NHR⁵, NHCOOA,        NA-acyl, NHCOOCH₂R⁵, NHSO₂CH₂R⁵, NHCOO-alkylene-OA, NH(CO)NA₂,        1-piperidinyl-CO—NH, 1-pyrrolidinyl-CONH, O(CH₂)_(n)COOA,        O(CH₂)_(n)COOH, O(CH₂)_(n)OH, O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH,        COOA, CH₂COOH or CH₂COOA,    -   R⁸ is a 5-7 membered heterocyclic radical having 1-4 N, O and/or        S atoms or        -   a            group,    -   G and Z are each, independently of one another, —CH═, N, O or S,    -   L is —CH═, —CH═CH— or —CH₂—CH₂—CH₂—,    -   Hal is fluorine, chlorine, bromine or iodine,    -   n is 0, 1 or 2, and    -   m is 1 or 2,    -   or a tautomeric cyclised form, and the (E)-isomers and the salts        of all isomers;    -   m) the compounds of the formula I described in WO 9841515        in which    -   X is O or S,    -   R¹ is H, Hal, OH, OA, A, NO₂, NH₂, NHA, NAA′, NHCOR⁴, NHCOR⁶,        NHSO₂R⁴, NHSO₂R⁶, S(O)_(m)R⁶, SO₃H, SO₂NR⁴R^(4′) or formyl,    -   R² and R^(2′) are each, independently of one another, A,        (CH₂)_(n)Ar, (CH₂)_(n)Het, CH₂COAr, CH₂COHet or OAr,    -   R^(2′) is additionally also H,    -   R³ is COOR⁴, CN, 1H-tetrazol-5-yl or CONHSO₂R⁵,    -   R⁴ and R^(4′) are each, independently of one another, H or A,    -   R⁵ is A or Ar,    -   R⁶ is phenyl or naphthyl, each of which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by A, NH₂, NHA,        NAA′, NO₂, CN or Hal,    -   R⁷ and R^(7′) are each, independently of one another, H or alkyl        having 1-6 carbon atoms,    -   A and A′ are each, independently of one another, alkyl having        1-6 carbon atoms, in which one or two CH₂ groups may be replaced        by O or S atoms or by —CR⁷═CR^(7′) groups and/or 1-7 H atoms may        be replaced by F, or benzyl,    -   Ar is phenyl or naphthyl, each of which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by A, OR⁴, NH₂,        NHA, NAA′, NO₂, CN, Hal, NHCOR⁴, NHCOR⁶, NHSO₂R⁴, NHSO₂R⁶,        COOR⁴, OPh, CONH₂, CONHA, CONAA′, COR⁴, CONHSO₂R⁴, CONHSO₂R⁶,        O(CH₂)_(n)COOR⁴, O(CH₂)_(n)OR⁴, SO₃H, SO₂NR⁴R^(4′), S(O)_(m)R⁶        or S(O)_(m)R⁴,    -   Het is a monocyclic or bicyclic saturated, unsaturated or        aromatic heterocyclic radical having 1-4 N, O and/or S atoms,        bonded via N or C, which may be unsubstituted or        monosubstituted, disubstituted or trisubstituted by Hal, A, R³,        NH₂, NHA, NAA′, NO₂ and/or ═O,    -   Hal is fluorine, chlorine, bromine or iodine,    -   m is 0, 1 or 2, and    -   n is 1 or 2,    -   where, if R² is CH₂COAr and R^(2′) is H, R³ is not COOA,    -   and salts thereof;    -   n) the compounds of the formula I described in WO 9841521        in which    -   Z is a single or double bond,    -   R¹ is a        group which is unsubstituted or monosubstituted in the phenyl        moiety by R⁷, or a        group which is unsubstituted or monosubstituted in the        cyclo-hexadienyl moiety by R⁷,    -   R² is A, Ar—(CH₂)_(m), cycloalkyl-(CH₂)_(m), Het-(CH₂)_(m) or        R¹—(CH₂)_(m),    -   R³ and R^(3′) are each, independently of one another, OR⁴,        NHSO₂R⁵, NH₂, NHA or NAA′,    -   R³ and R^(3′) together are alternatively —O—, forming a cyclic        anhydride,    -   R⁴ and R^(4′) are each, independently of one another, H or A,    -   R⁵ is A or Ar,    -   R⁶ is phenyl or naphthyl, each of which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by A, NH₂, NHA,        NAA′, NO₂, CN or Hal,    -   R⁷ is A, COOR⁴, CN, 1H-tetrazol-5-yl, CONHSO₂R⁵, Hal, OR⁴, NO₂,        NH₂, NHA, NAA′, NHCOR⁴, NHCOR⁶, NHSO₂R⁴, NHSO₂R⁶, S(O)_(k)R⁴,        S(O)_(k)R⁶, SO₂NR⁴R^(4′) or formyl,    -   R⁸ and R^(8′) are each, independently of one another, H or alkyl        having 1-6 carbon atoms,    -   E is CH₂ or O,    -   D is carbonyl or (CR⁴R^(4′))_(n),    -   E and D together are alternatively CR⁴═R^(4′),    -   X is S or O,    -   A and A′ are each, independently of one another, alkyl having        1-6 carbon atoms, in which one or two CH₂ groups may be replaced        by O or S atoms or by —CR⁸═CR^(8′)— groups and/or 1-7 H atoms        may be replaced by F,        -   or benzyl,    -   Ar is phenyl or naphthyl, each of which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by A, OR⁴, NH₂,        NHA, NAA′, NO₂, CN, Hal, NHCOR⁴, NHCOR⁶, NHSO₂R⁴, NHSO₂R⁶,        COOR⁴, OPh, CONH₂, CONHA, CONAA′, COR⁴, CONHSO₂R⁴, CONHSO₂R⁶,        O(CH₂)_(n)COOR⁴, O(CH₂)_(n)OR⁴, SO₂NR⁴R^(4′), S(O)_(k)R⁶ or        S(O)_(k)R⁴,    -   Het is a monocyclic or bicyclic saturated, unsaturated or        aromatic heterocyclic radical having 1-4 N, O and/or S atoms,        bonded via N or C, which may be unsubstituted or        mono-substituted, disubstituted or trisubstituted by Hal, A,        COOR⁴, CN, 1H-tetrazol-5-yl, CONHSO₂R⁵, NH₂, NHA, NAA′, NO₂        and/or ═O,    -   Hal is fluorine, chlorine, bromine or iodine,    -   k is 0, 1 or 2,    -   m is 0, 1 or 2, and    -   n is 1 or 2,    -   and the (Z)- and (E)-isomers and the salts of all isomers;    -   o) the compounds of the formula I described in WO 9842702        in which    -   R is    -   X and Y are each, independently of one another, O or S,    -   R¹ is H, Hal, OH, OA, A, alkylene-O-A, NO₂, NH₂, NH-acyl,        SO₂NH₂, SO₂-A, SO₂NHA, CN or formyl,    -   R², R³    -   and R⁴ are each, independently of one another, a phenyl group        which is unsubstituted or monosubstituted or polysubstituted by        Hal, OH, OA, O-alkylene-R⁵, A, S-A, S—OA, SO₂A, S—OR⁵, SO₂R⁵,        NO₂, NH₂, NHA, NA₂, NH-acyl, NHSO₂A, NHSO₂R⁵, NASO₂A, NASO₂—R⁵,        NH(CO)NH₂, NH(CO)NHA, formyl, NH(CO)NHR⁵, NHCOOA, NA-acyl,        NHCOOCH₂R⁵, NHSO₂CH₂R⁵, NHCOO-alkylene-OA, NH(CO)NA₂,        1-piperidinyl-CO—NH, 1-pyrrolidinyl-CONH, O(CH₂)_(n)COOA,        O(CH₂)_(n)COOH, O(CH₂)_(n)OH, O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH,        COOA, CH₂COOH or CH₂COOA,        -   a            group or a            group, where R² is additionally A or cycloalkyl,    -   R⁵ is a phenyl group which is unsubstituted or monosubstituted        or polysubstituted by Hal, OH, OA, A, S-A, NO₂, NH₂, NHA, NA₂,        NH-acyl, NHSO₂A, NASO₂A, NH(CO)NH₂, NH(CO)NHA, formyl, NHCOOA,        NA-acyl, NHCOO-alkylene-OA, NH(CO)NA₂, N-piperidinyl-CO—NH,        N-pyrrolidinyl-CONH, O(CH₂)_(n)COOA, O(CH₂)_(n)COOH,        O(CH₂)_(n)OH, O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH, COOA, CH₂COOH or        CH₂COOA,    -   A is alkyl having 1-6 carbon atoms, in which one or two CH₂        groups may be replaced by O or S atoms or by —CR⁶═CR^(6′)—        groups and/or 1-7 H atoms may be replaced by F,    -   D is carbonyl or [C(R⁶R^(6′))]_(m),    -   E is CH₂, S or O,    -   R⁶ and R^(6′) are each, independently of one another, H, F or A,    -   R⁷ is —O—C(═Y)—NH—R⁸,    -   R⁸ is alkyl having 1-10 carbon atoms which is unsubstituted or        monosubstituted or disubstituted by R⁹ and in which 1-2 carbon        atoms may be replaced by O and/or S and/or may be substituted by        ═O,        -   or        -   cycloalkyl, in which 1-2 carbon atoms may be replaced by N,            O and/or S    -   R⁹ is phenyl which is unsubstituted or monosubstituted or        disubstituted by Hal,        -   naphthyl, A-O—C(═O)— or Hal,    -   Hal is fluorine, chlorine, bromine or iodine,    -   n is 0, 1 or 2, and    -   m is 1 or 2,    -   and salts thereof;    -   p) the compounds of the formula I described in WO 9842709        in which    -   is N—R³, O or S,    -   R is 2,1,3-benzothiadiazol-4- or 5-yl or        2,1-benzoisothiazol-5-or 6-yl, each of which is unsubstituted or        monosubstituted or disubstituted by R² and/or R^(2′), or        -   phenyl which is unsubstituted or monosubstituted,            disubstituted or trisubstituted by R² and/or R^(2′),    -   R¹ is H or A,    -   R² and R^(2′) are each, independently of one another, H, A, OH,        OA, Hal, OCF₃, OCHF₂, —O—CO-A, —O-alkylene-COOR¹,        —O-alkylene-CH₂—OR¹,        -   or        -   OCH₂-phenyl or —O—CO-phenyl, each of which is unsubstituted            or monosubstituted or disubstituted in the phenyl moiety by            R⁴ and/or R^(4′),    -   R² and R^(2′) together are alternatively —OCH₂O—, —OCH₂CH₂O— or        —OCH₂CH₂—,    -   R³ is H, A, alkylene-O-A, —CO—OA, or alkylene-phenyl which is        unsubstituted or monosubstituted or disubstituted in the phenyl        moiety by R⁴ and/or R^(4′),    -   R⁴ and R^(4′) are each, independently of one another, H. A, OH,        OA, Hal, COOR¹ or CH₂OR¹,    -   A is alkyl having 1-6 carbon atoms,    -   Hal is fluorine, chlorine, bromine or iodine,    -   and salts thereof;    -   q) the compounds of the formula I described in WO 9905132        in which    -   R is    -   X is O or S,    -   R¹ is H, Hal, OA or A,    -   R², R³, R⁵ and R⁶ are each, independently of one another, H,        Hal, A, OA or R⁴,    -   R⁴ is —O—(CH₂)_(n)—Cy,    -   Cy is cycloalkyl having 3-8 carbon atoms,    -   A is alkyl having 1-6 carbon atoms, in which one or two CH₂        groups may be replaced by O or S atoms or by —CR⁵═CR^(5′)—        groups and/or 1-7 H atoms may be replaced by F,    -   R⁵ and R^(5′) are each, independently of one another, H, F or A,    -   Hal is fluorine, chlorine, bromine or iodine,    -   n is 0, 1 or 2,    -   or a tautomeric cyclised form, and the (E)-isomers and the salts        of all isomers,        for the preparation of a medicament for inhibiting the growth of        neoplastic cells.

The use of other endothelin receptor antagonists for the treatment oftumours is described, for example, in WO 99/06397, WO 98/57933 and WO96/06095.

The invention had the object of providing novel uses of medicaments inthe form of pharmaceutical preparations which have better propertiesthan known medicaments which can be used for the same purposes.

Surprisingly, it has been found that the compounds of the formulae Idescribed above are suitable for the treatment of cancer diseases.

The compounds of the formula I described above and salts thereof exhibitvery valuable pharmacological properties and are well tolerated. Thecompounds exhibit, inter alia, high affinity to the endothelinsub-receptors ET_(A) and ET_(B). These actions can be determined byconventional in-vitro or in-vivo methods, as described, for example, byP. D. Stein et al., J. Med. Chem. 37, 1994, 329-331 and E. Ohlstein etal., Proc. Natl. Acad. Sci. U.S.A 91, 1994, 8052-8056.

The compounds of the formula I can be employed as medicament activeingredients in human and veterinary medicine. They can furthermore beemployed as intermediates for the preparation of further medicamentactive ingredients.

The term “neoplastic cells” is taken to mean cancer cells.

Endothelin plays a role in the following types of cancer:

Prostate Cancer:

Prostate cancer cells secrete endothelin 1, patients with prostatecancer undergoing metastasis have a higher ET-1 plasma level, ET 1stimulates proliferation of various prostate cancer cell lines, ET-1stimulates osteo-blasts (Nelson J B et al. Nature Medicine 1/9 944-949,1995).

ET-1 stimulates bone formation in an osteoblast tumour model, ET-1influences metastasis formation by prostate cancer (Nelson JB et al.,Urology 53/5, 1064-1069, 1999).

Atrasentan (Abbott, endothelin A receptor antagonist) inhibits thegrowth of various prostate cancer cell lines in vitro (Nelson J B et al.Cancer Research 56, 663-668, 1996).

Ovarian Carcinoma:

Expression of endothelin 1 and endothelin A receptor (ETAR) in ovariancarcinomas, ET-1 stimulates proliferation of primary ovarian carcinomacells, BQ123 (selective endothelin A receptor antagonist) inhibits theproliferation of tumour cells (Bag nato A et al. Cancer Res 59, 720-727,1999). Expression of ET1 and ETAR in ovarian carcinomas (Salani D et al.American Journal of Pathology 157/5, 1537-1547, 2000).

ET-1 protects ovarian carcinoma cells against apoptosis. This can beeliminated by BQ123 (selective endothelin A receptor antagonist) (DelBufalo D et al., Molecular Pharmacology 61/3, 524532, 2002).

Intestinal Cancer:

Overexpression of ETAR in intestinal tumours (Ali H et al., Journal ofCardiovascular Pharmacology 36 S1 S69-S71, 2000).

ET-1 stimulates the proliferation of intestinal cancer cell lines. Thiscan be inhibited by BQ123 and BQ610 (selective endothelin Areceptorantago-nists) (Ali H et al. Gut 47, 685-688, 2000).

ET-1 is overexpressed in tumours in intestinal cancer patients. BQ123(selective endothelin A receptor antagonist) inhibits metastasisformation in a rat metastasis model (Asham E et al. British Journal ofCancer 81/11, 1759-1763, 2001).

Cervical Carcinoma:

HPV positive cervical carcinomas express ET-1 and overexpress endothelinA receptor. ET-1 stimulates proliferation of tumour cells. This can beinhibited by BQ123 (Venuti A et al., FASEB 14/14, 2279-2283, 2000).

Melanoma:

In melanomas, the endothelin B receptor is more important:

Melanoma cells overexpress endothelin B receptor.

Bosetan, an endothelin A and endothelin B receptor antagonist, inhibitsthe proliferation of melanoma cells in vitro (AACR Abstract No. 358,2002).

Pancreas:

Ro 61-612/001, an endothelin A and endothelin B receptor antagonist,inhibits the proliferation of pancreas tumour cells (ASPC-1) in vivo(AACR Abstract No. 3365, 2000, no paper published to date).

In-Vivo Experiment:

Testing of the substance in an ovarian carcinoma cell line analogouslyto AACR Abstract No. 2075, 2000: Rosano L et al., Inhibition of tumourgrowth and angiogenesis by ABT 627 an endothelin receptor A antagonistin ovarian carcinoma xenografts.

The effect of endothelin receptor antagonists in the treatment of cancercan also be determined by the method described by Shichiri et al. in J.Clin. Invest. 87, 1867 (1991).

The invention preferably relates to the use of endothelin receptorantagonists selected from the group consisting of

-   -   i) the compounds described in EP 0733626        -   a)            5-bromo-2-ethyl-N-(2,1,3-benzothiadiazol-5-yl)benzenesulfonamide;        -   b)            2,5-dichloro-N-(2,1,3-benzothiadiazol-5-yl)benzenesulfonamide;        -   c)            5-bromo-2-propyl-N-(2,1,3-benzothiadiazol-5-yl)benzenesulfonamide;        -   d)            5-dimethylamino-N-(2,1,3-benzothiadiazol-5-yl)naphthalenesulfonamide;        -   e)            5-dimethylamino-N-[6-methyl-(2,1,3-benzothiadiazol-5-yl)]-naphthalenesulfonamide;        -   f)            5-dimethylamino-N-[4-bromo-(2,1,3-benzothiadiazol-5-yl)]-naphthalenesulfonamide;        -   g)            5-dimethylamino-N-(2,1,3-benzothiadiazol-4-yl)naphthalenesulfonamide;        -   h)            5-dimethylamino-N-([1,2,5]-oxadiazole-[3,4-b]-pyridin-6-yl)naphthalenesulfonamide;        -   i)            5-dimethylamino-N-(1,2,5-benzoxadiazol-5-yl)-1-naphthalenesulfonamide;        -   j)            5-dimethylamino-N-(6-bromo-7-methyl-1,2,5-benzoxadiazol-5-yl)-1-naphthalenesulfonamide;        -   k)            2-phenyl-N-(2,1,3-benzothiadiazol-5-yl)benzenesulfonamide;    -   ii) the compounds described in EP 0758650        -   a)            2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)acetic            acid;        -   b)            2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)-N-(4-tert-butylphenylsulfonyl)acetamide;        -   c)            2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)-N-(4-isopropylphenylsulfonyl)acetamide;        -   d)            2-(1,3-benzodioxol-5-yl)-2-(7-propylquinolin-8-yloxy)acetic            acid;        -   e)            2-(1,3-benzodioxol-5-yl)-2-(7-propylquinolin-8-yloxy)-N-(4-tert-butylphenylsulfonyl)acetamide;        -   f) 2-(1,3-benzodioxol-5-yl)-2-(6-propylindol-7-yloxy)acetic            acid;        -   g)            2-(1,3-benzodioxol-5-yl)-2-(1-methyl-2-propylbenzimidazol-4-yloxy)acetic            acid;    -   iii) the compounds described in EP 0755934        -   a)            1,2-dihydro-1-(2-methoxybenzyl)-4-(4-methoxyphenyl)-2-oxo-benzofuro[3,2-b]pyridine-3-carboxylic            acid;        -   b)            2-(2-methoxybenzyloxy)-4-(4-methoxyphenyl)benzofuro[3,2-b]-pyridine-3-carboxylic            acid;        -   c)            4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(2-methoxybenzyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylic            acid;        -   d)            2-(2-methoxyphenoxy)-4-(4-methoxyphenyl)benzofuro[3,2-b]-pyridine-3-carboxylic            acid;        -   e)            4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(2-methoxybenzyl)-2-oxo-3-(1H-tetrazol-5-yl)benzofuro[3,2-b]pyridine;        -   f)            1,2-dihydro-1-(2,3-methylenedioxybenzyl)-4-(4-methoxyphenyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylic            acid;        -   g)            1,2-dihydro-1-(2,3-methylenedioxybenzyl)-7-methyl-4-(4-tri-fluoromethoxyphenyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylic            acid;        -   h)            1,2-dihydro-1-(2,3-methylenedioxybenzyl)-7-methyl-4-(4-methoxyphenyl)-2-oxobenzothieno[3,2-b]pyridine-3-carboxylic            acid;        -   i)            1,2-dihydro-1-(2,1,3-benzothiadiazol-5-methyl)-4-(4-methoxyphenyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylic            acid;    -   iv) the compounds described in EP 0757039        -   a)            4-(1,3-benzodioxol-5-yl)-1,2-dihydro-1-(2-methoxybenzyl)-2-oxoquinoline-3-carboxylic            acid;        -   b)            4-(1,3-benzodioxol-5-yl)-1,2-dihydro-1-(4-methoxybenzyl)-2-oxoquinoline-3-carboxylic            acid;        -   c)            4-(1,3-benzodioxol-5-yl)-1,2-dihydro-1-(3,4-methylenedioxybenzyl)-2-oxoquinoline-3-carboxylic            acid;        -   d)            4-(1,3-benzodioxol-5-yl)-1,2-dihydro-1-(2-methoxybenzyi)-2-oxoquinoline-3-acetic            acid;        -   e)            4-(1,3-benzodioxol-5-yl)-1,2-dihydro-1-(3,4-methylenedioxybenzyl)-2-oxoquinoline-3-acetic            acid;        -   f)            4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(2-methoxybenzyl)-2-oxoquinoline-3-carboxylic            acid;        -   g)            4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(4-methoxybenzyl)-2-oxoquinoline-3-carboxylic            acid;        -   h)            4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(6-chloro-3,4-methylenedioxybenzyl)-2-oxoquinoline-3-carboxylic            acid;        -   i)            4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(3,4-methylenedioxybenzyl)-2-oxoquinoline-3-carboxylic            acid;        -   j)            4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(3-methoxybenzyl)-2-oxoquinoline-3-carboxylic            acid;    -   v) the compounds described in EP 0796250        -   a)            2-(1,3-benzodioxol-5-yl)-2-(2,3-dihydro-4,6-dimethylpyridazin-3-on-2-yl)-N-(4-isopropylphenylsulfonyl)acetamide;        -   b)            2-(1,3-benzodioxol-5-yl)-2-(6-(4-methoxyphenyl)-2,3,4,5-tetra-hydropyridazin-3-on-2-yl)-N-(4-isopropylphenylsulfonyl)-acetamide;        -   c) 2-(1,3-benzodioxol-5-yl            )-2-(6-(4-chlorophenyl)-2,3,4,5-tetrahydropyridazin-3-on-2-yl)-N-(4-isopropylphenylsulfonyl)-acetamide;        -   d)            2-(1,3-benzodioxol-5-yl)-2-(6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-on-2-yl)-N-(4-isopropylphenylsulfonyl)-acetamide;        -   e)            2-(1,3-benzodioxol-5-yl)-2-(4-methyl-6-phenyl-2,3-dihydro-pyridazin-3-on-2-yl)-N-(4-isopropylphenylsulfonyl)acetamide;        -   f)            2-(1,3-benzodioxoi-5-yl)-2-(5-(3,4-dimethoxyphenyl)-6-ethyl-2H-3,6-dihydro-1,3,4-thiadiazin-2-on-3-yl)-N-(4-isopropylphenyl-sulfonyl)acetamide;    -   vi) the compounds described in WO 9719077        -   a)            3-(1,3-benzodioxol-5-yl)-1-(2,1,3-benzothiadiazol-5-ylmethyl)-5-propoxyindole-2-carboxylic            acid;        -   b)            3-(4-methoxyphenyl)-1-(2,1,3-benzothiadiazol-5-ylmethyl)-5-ethoxyindole-2-carboxylic            acid;        -   c)            3-(4-methoxyphenyl)-1-(2,1,3-benzothiadiazol-5-ylmethyl)-5-propoxyindole-2-carboxylic            acid;        -   d)            3-(2,1,3-benzothiadiazol-5-yl)-1-(4-methoxybenzyl)-5-ethoxyindole-2-carboxylic            acid;        -   e)            3-(2,1,3-benzothiadiazol-5-yl)-1-(4-methoxybenzyl)-5-propoxyindole-2-carboxylic            acid;        -   f)            3-(2,1,3-benzothiadiazol-5-yl)-1-(3,4-methylenedioxybenzyl)-5,6-dimethoxyindole-2-carboxylic            acid;    -   vii) the compounds described in WO 9730982        -   2-(2,1,3-benzothiadiazol-5-yl)-3-benzyl4-(4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4,5-trimethoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4-diisopropoxy-5-methoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-benzyl-4-(1,4-benzodioxan-6-yl)-4-oxo-2-butenoic            acid;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4,5-trimethoxybenzyl)-4-(1,4-benzodioxan-6-yl)-4-oxo-2-butenoic            acid;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4-diisopropoxy-5-methoxybenzyl)-4-(1,4-benzodioxan-6-yl)-4-oxo-2-butenoic            acid;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4,5-trimethoxybenzyl)-4-(1,3-benzodioxol-5-yl)-4-oxo-2-butenoic            acid;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-benzyl-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4,5-trimethoxybenzyl)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-[(7-methoxy-1,3-benzodioxol-5-yl)methyl]-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-methylthiobenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3-benzyloxy-4-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(2,3-dihydrobenzofuran-5-yl-methyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(2-methylpropyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxybenzyl)-5-hydroxy-5            -(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-tert-butoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-hydroxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-trifluoromethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-pentyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy4-hexyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-phenoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4,5-dimethoxy-3-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,5-dimethoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-chloro-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-methyl-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(2,5-dimethoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,3-dihydrobenzofuran-5-yl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-propoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(4-propoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(2,4-dimethoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-benzyloxy-2-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(2,3,4-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,4-dimethoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-triethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-difluoromethoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3-hydroxy-4-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(2,4-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(2,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-isopropoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-propoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-6-methyl-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-benzyloxy-benzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-hydroxy-benzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-propoxy-benzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,            1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-isopropoxybenzyl)-5-hydroxy-5-(1,4-benzodioxan-6-yl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-6-methyl-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-hexyloxybenzyl            )-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(1,4-benzodioxan-6-yl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3-methoxy-5-butoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2-fluoro-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-isopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-benzyloxy-benzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-fluoro-2-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-5-ethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-methoxycarbonylbenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3,-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-benzyloxyphenyl)-5H-furan-2-one;        -   3-(2,1,3,-benzothiadiazol-4-methyl-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isobutoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furna-2-one;        -   4-(2,1,3-benzothiadiazol-5-ylmethyl)-3-(7-methoxy-1,3-benzo-dioxol-5-yl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4-diisopropoxy-5-methoxybenzyl)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,5-dimethoxy-4-isopropoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4-dimethoxy-5-isopropoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,5-dimethoxy4-isopropoxybenzyl)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4,5-trimethoxybenzyl)-4-(⁴-methoxyphenyl)-4-oxo-2-butenoic            acid;    -   viii) the compounds described in WO 9730996        -   a)            3-(2,1,3-benzothiadiazol-5-aminosulfonyl)-N-(6-methyl-1,3-benzodioxol-5-yl)thiophene-2-carboxamide;        -   b)            3-(2,1,3-benzothiadiazol-5-aminosuifonyl)-N-(6-acetyl-1,3-benzodioxol-5-yl)thiophene-2-carboxamide;        -   c)            3-(2,1,3-benzothiadiazol-5-aminosulfonyl)-N-(6-cyano-1,3-benzodioxol-5-yl)thiophene-2-carboxamide;        -   d)            3-(2,1,3-benzothiadiazol-5-aminosulfonyl)-2-(6-methyl-1,3-benzodioxol-5-ylmethylcarbonyl)thiophene;    -   ix) the compounds described in DE 19609597        -   a)            N-(2,1,3-benzothiadiazol-5-yl)-5-N′-isopropylamino-1-naphthalenesulfonamide;        -   b)            N-(2,1,3-benzothiadiazol-5-yl)-5-N′-propylamino-1-naphthalenesulfonamide;        -   c)            N-(2,1,3-benzothiadiazol-5-yl)-5-N′-methylamino-1-naphthalenesulfonamide;        -   d)            N-(2,1,3-benzothiadiazol-5-yl)-5-N′-ethylamino-1-naphthalenesulfonamide;        -   e)            N-(2,1,3-benzothiadiazol-5-yl)-5-N′-butylamino-1-naphthalenesulfonamide;    -   x) the compounds described in DE 19612101        -   a)            4-(4-methoxyphenyl)-1,6-dihydro-1-(2-methoxybenzyl)-2-methyl-6-oxopyrimidine-5-carboxylic            acid;        -   b)            4-(3,4-methylenedioxyphenyl)-1,6-dihydro-1-(2-methoxybenzyl)-2-cyclopropyl-6-oxopyrimidine-5-carboxylic            acid;        -   c)            4-(2-carboxy4-methoxy-7-benzofurnayl)-1,6-dihydro-1-(2-methoxybenzyl)-2-methyl-6-oxopyrimidine-5-carboxylic            acid;        -   d)            4-(2-phenyl-4-methoxyphenyl)-1,6-dihydro-1-(2-methoxybenzyl)-2-methyl-6-oxopyrimidine-5-carboxylic            acid;        -   e)            4-(2-carboxy-4-methoxy-7-benzofuranyl)-1,6-dihydro-1-(5-benzothiadiazolyl)-2-methyl-6-oxopyrimidine-5-carboxylic            acid;        -   f)            4-(4-methoxyphenyl)-1,6-dihydro-1-(5-benzothiadiazolyl)-2-methyl-6-oxopyrimidine-5-carboxylic            acid;    -   xi) the compounds described in WO 9827091        -   a)            4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-benzyl-3-butyl-1H-pyrazole-5-carboxylic            acid;        -   b)            4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-methoxybenzyl)-3-butyl-1H-pyrazole-5-carboxylic            acid;        -   c)            4-(2,1,3-benzothiadiazol-6-chloro-5-ylmethyl)-1-(3-methoxybenzyl)-3            -butyl-1H-pyrazole-5-carboxylic acid;        -   d)            4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(2-carboxymethoxy-4-methoxybenzyl)-3-butyl-1H-pyrazole-5-carboxylic            acid;        -   e)            4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(2,4-dimethoxybenzyl)-3-butyl-1H-pyrazole-5-carboxylic            acid;        -   f)            4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-methoxybenzyl)-3-phenyl-1H-pyrazole-5-carboxylic            acid;        -   g)            4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-methoxybenzyl)-3-(2-thienyl)-1H-pyrazole-5-carboxylic            acid;        -   h)            4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-methoxybenzyl)-3-cyclohexyl-1H-pyrazole-5-carboxylic            acid;        -   i)            4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(2-carboxymethoxy4-methoxybenzyl)-3-propoxy-1H-pyrazole-5-carboxylic            acid;    -   xii) the compounds described in WO 9827077        -   a)            2-(2,1,3-benzothiadiazol-5-yl)-3-(thien-2-ylmethyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   b)            2-(2,1,3-benzothiadiazol-5-yl)-3-(5-methoxythien-2-ylmethyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   c)            3-(2,1,3-benzothiadiazol-5-yl)-4-(furan-2-ylmethyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;.        -   d)            3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-5H-furan-2-one;        -   e)            3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-5H-furan-2-one;        -   f)            3-(2,1,3-benzothiadiazol-5-yl)-4-(thien-3-ylmethyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;    -   xiii) the compounds described in WO 9841515        -   a)            2-(2,1,3-benzothiadiazol-5-yl)-4-(4-methoxyphenyl)-4-oxo-2-butanoic            acid;        -   b)            2-(2,1,3-benzothiadiazol-5-yl)-3-(2,1,3-benzothiadiazol-5-yl-methyl)acetic            acid;        -   c)            2-(2,1,3-benzothiadiazol-5-yl)-2-(4-methoxycarbonylbenzyl)-acetic            acid;        -   d)            2-(2,1,3-benzothiadiazol-5-yl)-2-(4-methoxycarbonylbenzyl)-N-(4-isopropylphenyisulfonyl)acetamide;        -   e)            2-(2,1,3-benzothiadiazol-5-yl)-2-(4-carboxybenzyl)-N-(4-isopropylphenylsulfonyl)acetamide;        -   f) 2-(2,1,3-benzothiadiazol-5-yl)-4-(4-methoxybenzyl)acetic            acid;        -   g)            2-(2,1,3-benzothiadiazol-5-yl)-2-(4-methoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butanoic            acid;    -   xiv) the compounds described in WO 9841521        -   a)            2-(1,3-benzodioxol-5-yl)-3-(2,1,3-benzothiadiazol-5-yl)-succinic            acid;        -   b) 2,3-bis(1,3-benzodioxol-5-yl)maleic acid;        -   c) N,N-dibutyl-2,3-bis(1,3-benzodioxol-5-yl)maleamide;        -   d) 2,3-bis(1,3-benzodioxoi-5-yl)maleic anhydride;.        -   e) 2-(1,3-benzodioxol-5-yl)-3-phenylmaleic anhydride;    -   xv) the compounds described in WO 9842702        -   ethyl            [3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-(4-methoxyphenyl)-5H-furan-2-on-5-yloxycarbonylamino]-acetate;        -   ethyl            [3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-(3-fluoro4-methoxyphenyl)-5H-furan-2-on-5-yloxycarbonyl-amino]acetate;        -   N-1-naphthylethyl-[3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-(3-fluoro-4-methoxyphenyl)-5H-furna-2-on-5-yl]carbamate;        -   ethyl            2-[3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-on-5-yloxycarbonyl-amino]-3-methylbutyrate;        -   2-(2,1,3-benzothiadiazol-5-yl)-3-(3-fluoro-4-methoxybenzoyl)-4-(3,4,5-trimethoxyphenyl)but-2-enoic            acid;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-benzyl-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furna-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-[(7-methoxy-1,3-benzodioxol-5-yl)methyl]-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2-methoxyphenyl)-5H-furna-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-methylthiobenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3-benzyloxy-4-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(2,3-dihydrobenzofuran-5-yl-methyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(2-methylpropyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-tert-butoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-hydroxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furna-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-trifluoromethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isopropoxy-benzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;

3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-pentyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;

-   -   -   3-(2,1,3-benzothiadiazol-5-yl            )-4-(3,5-dimethoxy-4-hexyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-phenoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4,5-dimethoxy-3-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl            )-5H-furna-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,5-dimethoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-chloro-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-methyl-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(2,5-dimethoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,3-dihydrobenzofuran-5-yl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy4-isopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;

    -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-propoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(4-propoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(2,4-dimethoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-benzyloxy-2-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(2,3,4-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,4-d            imethoxyphenyl)-5H-furna-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-triethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-difluoromethoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3-hydroxy-4-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furna-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(2,4-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(2,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-isopropoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-propoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3,-benzothiadiazol-6-methyl-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy4-benzyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-hydroxybenzyl)-5-hydroxy-5-(4-methoxypheriyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-propoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-isopropoxybenzyl)-5-hydroxy-5-(1,4-benzodioxan-6-yl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-6-methyl-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-hexyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(1,4-benzodioxan-6-yl            )-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3-methoxy-5-butoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxybenzyl)-5hydroxy-5-(4-rhethoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl            )-4-(3,4,5-trimethoxybenzyl)-5hydroxy-5-(2-fluoro-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-isopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-benzyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-fluoro-2-methoxyphenyl            )-5H-furna-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-5-ethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(4-methoxycarbonylbenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxybenzyl)-5-hydroxy-5-(3-fluoro4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-benzyloxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-4-methyl-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isobutoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   4-(2,1,3-benzothiadiazol-5-yl)-3-(7-methoxy-1,3-benzodioxol-5-yl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;

    -   and the open-chain tautomers;

    -   xvi) the compounds described in WO 9842709        -   a)            3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(4-methoxyphenyl)-8-methyl-3,8-dihydro-3,8-diazacyclopenta[a]indene-2-carboxylic            acid;        -   b)            3-(2-methoxybenzyl)-1-(4-methoxyphenyl)-8-methyl-3,8-dihydro-3,8-diazacyclopenta[a]indene-2-carboxylic            acid;        -   c)            3-(2,5-dimethoxybenzyl)-1-(4-methoxyphenyl)-8-methyl-3,8-dihydro-3,8-diazacyclopenta[a]indene-2-carboxylic            acid;        -   d)            3-(1,3-benzodioxol-5-ylmethyl)-1-(4-methoxyphenyl)-8-methyl-3,8-dihydro-3,8-diazacyclopenta[a]indene-2-carboxylic            acid;        -   e)            3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(4-methoxyphenyl)-8-oxa-3-azacyclopenta[a]indene-2-carboxylic            acid;        -   f)            3-(2,1,3,-benzothiadiazol-5-ylmethyl)-1-(4-methoxyphenyl)-8-thia-3-azacyclopenta[a]indene-2-carboxylic            acid;        -   g)            3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-carboxymethoxy-4-methoxyphenyl)-8-methyl-3,8-dihydro-3,8-diazacyclopenta[a]-indene-2-carboxylic            acid;        -   h)            3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-carboxymethoxy-4-methoxyphenyl)-8-oxa-3-azacyclopenta[a]indene-2-carboxylic            acid;        -   i)            3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-carboxymethoxy4-methoxyphenyl)-8-thia-3-azacyclopenta[a]indene-2-carboxylic            acid;

    -   xvii) the compounds described in WO 9905132        -   a)            2-(2,1,3-benzothiadiazol-5-yl)-3-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   b)            2-(2,1,3-benzothiadiazol-5-yl)-3-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-butenoic            acid;        -   c)            3-(2,1,3-benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;        -   d)            3-(2,1,3-benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;        -   e)            3-(2,1,3-benzothiadiazol-5-yl)-4-(3-cyclopentyloxy-4,5-dimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;        -   f)            3-(7-methyl-2,1,3-benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;

    -   and physiologically acceptable salts and/or solvates thereof for        the preparation of a medicament for inhibiting the growth of        neoplastic cells.

The invention relates, in particular, to the use of endothelin receptorantagonists selected from the group consisting of

-   -   a)        5-dimethylamino-N-(2,1,3-benzothiadiazol-5-yl)naphthalenesulfon-amide;    -   b)        2-(2,1,3-benzothiadiazol-5-yl)-3-(3-fluoro-4-methoxybenzoyl)-4-(3,4,5-trimethoxyphenyl)but-2-enoic        acid;    -   and physiologically acceptable salts and/or solvates thereof for        the preparation of a medicament for inhibiting the growth of        neoplastic cells.

For inhibiting the growth of neoplastic cells and for the treatment oftumour diseases, particular preference is given to the use of endothelinreceptor antagonists which have high affinity to the ET_(A) receptor.

The invention furthermore relates to the use of the compounds of theformula I and the preferred compounds described above andphysiologically acceptable salts and/or solvates thereof for thepreparation of a medicament for the treatment and/or prophylaxis ofcancer diseases.

The invention furthermore relates to the use of the said compounds,where the cancer diseases are selected from the group consisting ofprostate cancer, ovarian carcinoma, intestinal cancer, cervicalcarcinoma, melanoma and pancreatic cancer.

The invention furthermore relates to the use of the compounds of theformula I and the preferred compounds described aboveand-physiologically acceptable salts and/or solvates thereof for thepreparation of a medicament for the treatment of neoplastic damage.

The invention furthermore relates to the use of the compounds of theformula I and the preferred compounds described above andphysiologically acceptable salts and/or solvates thereof for thepreparation of a medicament for the treatment of precancerogenic damage.

The term “precancerogenic damage” is taken to mean, for example, benigntumours in the intestine which can result in intestinal cancer.

The term “precancerogenic damage” is taken to mean, in particular, thelesions mentioned in U.S. Pat. No. 5,948,911 at column 4, lines 49-60.

Irregularities in apoptosis (cell death) play a role in the formation ofpre-cancerogenic damage.

It is also known that the regulation of apoptosis plays an importantrole in diseases connected with abnormal cell growth, such as, forexample, benign prostate hyperplasia, neurodegenerative diseases, suchas, for example, Parkinson's, autoimmune diseases, including multiplesclerosis, and rheumatoid arthritis, or infection diseases, such asAIDS.

The compounds of the formula I modulate apoptosis and are used in thetreatment or prophylaxis of cancer diseases.

The invention thus relates to the use of the compounds of the formula Idescribed and the preferred compounds described above andphysiologically acceptable salts and/or solvates thereof for thepreparation of a medicament for regulating apoptosis in human cells.

The invention furthermore relates to the use of the compounds of theformula I and the preferred compounds described above and/orphysiologically acceptable salts thereof for the preparation ofpharmaceutical preparations, in particular by non-chemical methods. Theycan be converted into a suitable dosage form here together with at leastone solid, liquid and/or semi-liquid excipient or adjuvant andoptionally in combination with one or more further active ingredients.

These preparations can be used as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration and do not react with the novel compounds, for examplewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatine, carbohydrates, such as lactoseor starch, magnesium stearate, talc or Vaseline. Suitable for oraladministration are, in particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders. The novel compounds mayalso be lyophilised and the resultant lyophilisates used, for example,for the preparation of injection preparations. The preparationsindicated may be sterilised and/or comprise adjuvants, such aslubricants, preservatives, stabilisers and/or wetting agents,emulsifiers, salts for modifying the osmotic pressure, buffersubstances, colorants and flavours and/or a plurality of further activeingredients, for example one or more vitamins. They can furthermore beadministered as nasal sprays.

The substances are in general preferably administered here in doses ofbetween about 1 and 500 mg, in particular between 5 and 100 mg perdosage unit. The daily dose is preferably between about 0.02 and 10mg/kg of body weight. However, the specific dose for each patientdepends on a wide variety of factors, for example on the efficacy of thespecific compound employed, on the age, body weight, general state ofhealth, sex, on the diet, on the time and method of administration, onthe excretion rate, medicament combination and severity of theparticular disease to which the therapy applies. Oral administration ispreferred.

1. Use of endothelin receptor antagonists selected from the groupconsisting of a) the compounds of the formula I described in EP 0733626

in which -A=B—C=D- is a —CH═CH—CH═CH— group in which 1 or 2 CH has(have) been replaced by N, Ar is Ph or naphthyl, each of which isunsubstituted or monosubstituted, disubstituted or trisubstituted by H,Hal, A, alkenyl having up to 6 carbon atoms, Ph, OPh, NO₂, NR⁴R⁵,NHCOR⁴, CF₃, OCF₃, CN, OR⁴, COOR⁴, (CH₂)_(n)COOR⁴, (CH₂)_(n)NR⁴R⁵,—N═C═O or NHCONR⁴R⁵, R¹,R² and R³ are each, independently of oneanother, absent, H, Hal, A, CF₃, NO₂, NR⁴R⁵, CN, COOR⁴ or NHCOR⁴, R⁴ andR⁵ are each, independently of one another, H or A, or together arealternatively —CH₂—(CH₂)_(n)—CH₂—, A is alkyl having from 1 to 6 carbonatoms, Ph is phenyl, X is O or S, Hal is F, Cl, Br or I, n is 1, 2 or 3,and the salts thereof; b) the compounds of the formula I described in EP0758650

in which X is a saturated, fully unsaturated or partially unsaturated3-to 4-membered alkylene chain, in which from 1 to 3 carbon atoms may bereplaced by N and/or 1 or 2 carbon atoms may be replaced by 1-2 O atomsand/or 1-2 S atoms, but where at most up to 3 carbon atoms are replacedand where, in addition, a monosubstitution, disubstitution ortrisubstitution of the alkylene chain and/or of a nitrogen locatedtherein by A, R⁸ and/or NR⁴R⁴ may occur, and where, furthermore, one CH₂group in the alkylene chain may also be replaced by a C═O group, A isalkyl having 1-6 carbon atoms, in which one or two CH₂ groups may bereplaced by O or S atoms or by —CR⁴═CR^(4′)— groups and in addition 1-7H atoms may be replaced by F, R¹ is H or A, R² is COOR⁴, CN,1H-tetrazol-5-yl or CONHSO₂R⁸, R³ is Ar, R⁴ and R^(4′) are each,independently of one another, H, alkyl having from 1 to 6 carbon atomsor benzyl, Ar is phenyl or naphthyl, each of which is unsubstituted ormonosubstituted, disubstituted or trisubstituted by R⁵, R⁶ or R⁷, or a

group which is unsubstituted or monosubstituted or disubstituted by inthe phenyl moiety R⁵ or R⁶, R⁵, R⁶ and R⁷ are each, independently of oneanother, R⁴, OR⁴, Hal, CF₃, OCF₃, OCHF₂, OCH₂F, NO₂, NR⁴R^(4′), NHCOR⁴,CN, NHSO₂R⁴, COOR⁴, COR⁴, CONHSO₂R⁸, O(CH₂)_(n)R², OPh, O(CH₂)_(n)OR⁴ orS(O)_(m)R⁴, R⁸ is phenyl or naphthyl, each of which is unsubstituted ormonosubstituted, disubstituted or trisubstituted by A, OR¹, NR⁴R^(4′) orHal, E is CH₂ or O, D is carbonyl or [C(R⁴R^(4′))]_(n), Hal is F, Cl, Bror I, m is 0, 1 or 2, n is 1 or 2, and salts thereof; c) the compoundsof the formula I described in EP 0755934

in which —Y-Z- is —NR⁷—CO—, —N═C(OR⁷)— or —N═CR⁸—, R¹ is Ar, R² isCOOR⁶, CN, 1H-tetrazol-5-yl or CONHSO₂Ar, R³, R⁴ and R⁵ are each,independently of one another, R⁶, OR⁶, S(O)_(m)R⁶, Hal, NO₂, NR⁶R^(6′),NHCOR⁶, NHSO₂R⁶, OCOR⁶, COOR⁶ or CN, R⁶ and R^(6′) are each,independently of one another, H, alkyl having from 1 to 6 carbon atoms,benzyl or phenyl, R⁷ is (CH₂)_(n)Ar, R⁸ is Ar or OAr, Ar is phenyl whichis unsubstituted or monosubstituted, disubstituted or trisubstituted byR⁹, R¹⁰ or R¹¹, or unsubstituted naphthyl, or a

group which is unsubstituted or monosubstituted or disubstituted in thephenyl moiety by R⁹ or R¹⁰, or a

group which is unsubstituted or monosubstituted or disubstituted in thecyclohexadienyl moiety by R⁹ or R¹⁰, R⁹ R¹⁰ and R¹¹ are each,independently of one another, R⁶, OR⁶, Hal, CF₃, OCF₃, OCHF₂, OCH₂F,NO₂, NR⁶R^(6′), NHCOR⁶, CN, NHSO₂R⁶, COOR⁶, COR⁶, CONHSO₂Ar,O(CH₂)_(n)R², O(CH₂)_(n)OR⁶ or S(O)_(m)R⁶, E is CH₂,S or O, D iscarbonyl or [C(R R^(6′))]_(n), Hal is F, Cl, Br or I, X is O or S, m is0, 1 or 2, n is 1 or 2, and salts thereof; d) the compounds of theformula I described in EP 0757039

in which —Y-Z- is —NR⁷—CO—, —N═C(OR⁷)— or —N═CR⁸—, R¹ is Ar, R² isCOOR⁶, (CH₂)_(n)COOR⁶, CN, 1H-tetrazol-5-yl or CONHSO₂Ar, R³, R⁴ and R⁵are each, independently of one another, R⁶, OR⁶, S(O)_(m)R⁶, Hal, NO₂,NR⁶R^(6′), NHCOR⁶, NHSO₂R⁶, OCOR⁶, COR⁶, COOR6 or CN, where R³ and R⁴together can alternatively be an O(CH₂)_(n)) group, R⁶ and R^(6′) areeach, independently of one another, H, alkyl having from 1 to 6 carbonatoms, benzyl or phenyl, R⁷ is (CH₂)_(n)Ar, R⁸ is Ar or OAr, Ar isphenyl which is unsubstituted or monosubstituted, disubstituted ortrisubstituted by R⁹, R¹⁰ or R¹¹, or unsubstituted naphthyl, or a

group which is unsubstituted or monosubstituted or disubstituted in thephenyl moiety by R⁹ or R¹⁰, or a

group which is unsubstituted or monosubstituted or disubstituted in thecyclohexadienyl moiety by R⁹ or R¹⁰, R⁹, R¹⁰ and R¹¹ are each,independently of one another, R⁶, OR⁶ Hal, CF₃, OCF₃, OCHF₂, OCH₂F, NO₂,NR⁶R^(6′), NHCOR⁶, CN, NHSO₂R⁶, COOR⁶, COR⁶, CONHSO₂Ar, O(CH₂)_(n)R²,O(CH₂)_(n)OR⁶ or S(O)_(m)R^(l ,) E is CH₂, S or O, D is carbonyl or[C(R⁶R^(6′))]_(n), X is O or S, Hal is F, Cl, Br or I, m is 0, 1 or 2, nis 1, 2 or 3, and salts thereof; e) the compounds of the formula Idescribed in EP 0796250

in which Y is —C(R⁴R^(4′))—C(R⁴R^(4′))—, —CR⁴═CR^(4′)— or—C(R⁴R^(4′))—S—, R¹ is Het, Ar, R³ or R⁴, R² is Ar or a

group which is unsubstituted or monosubstituted or disubstituted in thephenyl moiety by A, R³, OR⁴, NH₂, NHA, NA₂, NO₂, CN, Hal, NHCOR⁴,NHSO₂R⁴, COOR⁴, COR⁴, CONHSO₂R⁶, O(CH₂)_(n)R³, OPh, O(CH₂)_(n)OR⁴ orS(O)_(m)R⁴, or a

group which is unsubstituted or monosubstituted or disubstituted in thecyclohexadienyl moiety by A, R³, OR⁴, NH₂, NHA, NA₂, NO₂, CN, Hal,NHCOR⁴, NHSO₂R⁴, COOR⁴, COR⁴, CONHSO₂R⁶, O(CH₂)_(n)R³, OPh,O(CH₂)_(n)OR⁴ or S(O)_(m)R⁴, R³ is CN, COOH, COOA, CONHSO₂R⁵or1H-tetrazol-5-yl, R⁴ and R^(4′) are each, independently of one another,H, A, or phenyl or benzyl, each of which is unsubstituted ormonosubstituted by alkoxy, R⁵ is A or Ar, R⁶ is phenyl or naphthyl, eachof which is unsubstituted or monosubstituted, disubstituted ortrisubstituted by A, OR⁵, NH₂, NHA, NA₂, NO₂, CN or Hal, A is alkylhaving 1-6 carbon atoms, in which one or two CH₂ groups may be replacedby O or S atoms or by —CR⁴═CR⁴— groups and in addition 1-7 H atoms maybe replaced by F, or benzyl, Ar is phenyl or naphthyl, each of which isunsubstituted or monosubstituted, disubstituted or trisubstituted by A,OR⁴, NH₂, NHA, NA₂, NO₂, CN, Hal, NHCOR⁴, NHSO₂R⁴, COOR⁴, COR⁴,CONHSO₂R⁶, O(CH₂)_(n)R³, OPh, O(CH₂)_(n)OR⁴ or S(O)_(m)R⁴, Het is amonocyclic or bicyclic saturated, unsaturated or aromatic heterocyclicradical having from 1 to 4 N, O and/or S atoms, bonded via N or C, whichmay be unsubstituted or monosubstituted, disubstituted or trisubstitutedby Hal, A, R³, NH₂, NHA, NA₂, CN, NO₂ and/or carbonyl oxygen, D iscarbonyl or [C(R⁴R^(4′))]_(n), E is CH₂, S or O, Hal is F, Cl, Br or I,X is O or S, m is 0, 1 or 2, n is 1 or 2, and salts thereof; f) thecompounds of the formula I described in WO 9719077

in which R is

X is O or S, R is H, Hal, OH, OA, A, alkylene-O-A, NO₂, NH₂, NH-acyl,SO₂NH₂, SO₃-A, SO₂NHA, CN or formyl, R² is H or A, R³, R⁵, R⁶, R⁷ and R⁸are each, independently of one another, H, Hal, OH, OA, O-alkylene-R⁴,A, S-A, NO₂, NH₂, NHA, NA₂, NH-acyl, NHSO₂A, NHSO₂R⁴, NASO₂A, NASO₂—R⁴,NH(CO)NH₂, NH(CO)NHA, formyl, NH(CO)NH-phenyl, NHCOOA, NA-acyl, NHR⁴,NHCOOR⁴, NHCOO-benzyl, NHSO₂-benzyl, NHCOO-alkylene-OA, NH(CO)NA₂,N-piperidinyl-CO—NH, N-pyrrolidinyl-CONH, O(CH₂)_(n)COOR², O(CH₂)_(n)OR, CH₂OH or CH₂OA, R³ and R⁶ together are alternatively —O—CH₂—O—,—O—CH₂—CH₂—O—, —O—CH₂—CH₂—, O—CF₂—O— or —O—CF₂—CF₂—O—, R⁴ is phenylwhich is unsubstituted or monosubstituted or polysubstituted by R³and/or R⁶, A is alkyl having 1-6 carbon atoms, Hal is fluorine,chlorine, bromine or iodine, n is 1 or 2, and salts thereof; g) thecompounds of the formula I described in WO 9730982

in which R is

X is O or S, R¹ is H, Hal, OH, OA, A, alkylene-O-A, NO₂, NH₂, NH-acyl,SO₂NH₂, SO₃-A, SO₂NHA, CN or formyl, R², R³ and R⁴ are each,independently of one another, a phenyl group which is unsubstituted ormonosubstituted or polysubstituted by Hal, OH, OA, O-alkylene-R⁵, A,S-A, SOA, SO₂A, SOR⁵, SO₂R⁵, NO₂, NH₂, NHA, NA₂, NH-acyl, NHSO₂A,NHSO₂R⁵, NASO₂A, NASO₂—R⁵, NH(CO)NH₂, NH(CO)NHA, formyl, NH(CO)NHR⁵,NHCOOA, NA-acyl, NHCOOCH₂R⁵, NHSO₂CH₂R⁵, NHCOO-alkylene-OA, NH(CO)NA₂,1-piperidinyl-CO-NH, 1-pyrrolidinyl-CONH, O(CH₂)_(n)COOA,O(CH₂)_(n)COOH, O(CH₂)_(n)OH, O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH, COOA,CH₂COOH or CH₂COOA, a

group or a

group, where is additionally A or cycloalkyl, R⁵ is a phenyl group whichis unsubstituted or monosubstituted or polysubstituted by Hal, OH, OA,A, S-A, NO₂, NH₂, NHA, NA₂, NH-acyl, NHSO₂A, NASO₂A, NH(CO)NH₂,NH(CO)NHA, formyl, NHCOOA, NA-acyl, NHCOO-alkylene-OA, NH(CO)NA₂,N-piperidinyl-CO—NH, N-pyrrolidinyl-CON H, O(CH₂)_(n)COOA,O(CH₂)_(n)COOH, O(CH₂)_(n)OH, O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH, COOA,CH₂COOH or CH₂COOA, A is alkyl having 1-6 carbon atoms, in which one ortwo CH₂ groups may be replaced by O or S atoms or by —CR⁶═CR⁶— groupsand/or 1-7 H atoms may be replaced by F, D is carbonyl or[C(R⁶R^(6′))]_(m), E is CH₂, S or O, Y is O or S, R⁶ and R^(6′) areeach, independently of one another, H, F or A, Hal is fluorine,chlorine, bromine or iodine, n is 1 or 2, and m is 1 or 2, or atautomeric cyclised form, and the (E)-isomers and the salts of allisomers; h) the compounds of the formula I described in WO 9730996

in which -A=B—C=D- is a —CH═CH—CH═CH— group, in which, in addition, 1 or2 CH may be replaced by N, Het is a monocyclic or bicyclic saturated,unsaturated or aromatic heterocyclic radical having from 1 to 4 N, Oand/or S atoms which is unsubstituted or substituted by -Z-R⁶, R¹, R²and R³ are each, independently of one another, absent, H, Hal, A, CF₃,NO₂, NR⁴R⁵, CN, COOR⁴ or NHCOR⁴, R⁴ and R⁵ are each, independently ofone another, H or A, or together are alternatively —CH₂—(CH₂)_(n)—CH₂—,R⁶ is a phenyl radical, a benzothiadiazol-5-yl radical or abenzoxadiazol-5-yl radical, each of which is unsubstituted ormonosubstituted, disubstituted or trisubstituted by R⁷, R⁸ and/or R⁹,R⁷, R⁸ and R⁹ are each, independently of one another, A, O-A, CN, COOH,COOA, Hal, formyl or —CO-A, and R⁷ and R⁸ together are alternatively—O—(CH₂)_(m)—O—, A is alkyl having from 1 to 6 carbon atoms, X is O orS, Z is —CO—, —CONH—, —CO—(CH₂)_(n)—, —CH═CH—, —(CH₂)_(n)—,—CONHCO—,—NHCONH—, —NHCOO —, —O—COHN—, —CO—O— or —O—CO—, Hal is F, Cl,Br or I, m is 1 or 2, and n is 1, 2 or 3, and salts thereof; i) thecompounds of the formula I described in DE 19609597

in which Ar is naphthyl which is monosubstituted by NH₂, NHA or NA₂, andA is alkyl having from 1 to 6 carbon atoms, and physiologicallyacceptable salts thereof; j) the compounds of the formula I described inDE 19612101

in which —Y-Z- is —NR⁴—Co or —N═CR⁵—, R¹ is Ar, R² is H, alkyl having1-6 carbon atoms which is unsubstituted or monosubstituted,disubstituted or trisubstituted by OR³ or Hal, or (CH₂)_(m)Ph or(CH₂)_(m)-cycloalkyl, each of which is unsubstituted or monosubstituted,disubstituted or trisubstituted by R³, OR³ or Hal, R³ and R^(3′) areeach, independently of one another, H, alkyl having 1-6 carbon atoms orbenzyl, R⁴ is CH₂Ar, ^(R5) is OCH₂Ar, Ar is phenyl which isunsubstituted or monosubstituted, disubstituted or trisubstituted by R⁶,R⁷ or R⁸, or a

group which is unsubstituted or monosubstituted in the phenyl moiety byR⁶, or a

group which is unsubstituted or monosubstituted in the cyclohexadienylmoiety by R⁶, E is CH₂ or O, D is carbonyl or (CH₂)_(n), E and Dtogether are alternatively CH═CR⁹, R⁶ and R^(6′) are each, independentlyof one another, R³, OR³or Hal, R⁷ is R³, OR³, Hal, NO₂, NH₂, NHR³,NR³R^(3′), NHCOR³, COOR³, O(CH₂)_(n)R³ or O(CH₂)_(n)OR³, R⁸ is Ph whichis unsubstituted or monosubstituted, disubstituted or trisubstituted byR³, OR³, Hal, NO₂, NH₂, NHR⁶, NR⁶R^(6′), NHCOR³ or COOR³, R⁹ is H, OH,CH₂OH or COOR³, Hal is F, Cl, Br or I, Ph is phenyl, m is 0 or 1, n is 1or 2, and salts thereof; k) the compounds of the formula I described inWO 9827091

in which R is phenyl which is unsubstituted or monosubstituted,disubstituted or trisubstituted by R³, R⁴ or R⁵ or is2,1,3-benzothiadiazolyl which is unsubstituted or monosubstituted by R²,R¹ is A, in which 1-7 H atoms may be replaced by F, or is —S-A or —O-A,or phenyl or -alkylene-phenyl, each of which is unsubstituted ormonosubstituted by R³, or thienyl which is unsubstituted ormonosubstituted by R³, R² is A, F, Cl, Br or —O-A, R³, R⁴ and R⁵ areeach, independently of one another, A, —O-A, —S-A, —O-alkylene-COOH,-alkylene-COOH or COOH, R³ and R⁴ together are alternatively —O—CH₂—O—,and A is alkyl having 1-7 carbon atoms, and salts thereof; I) thecompounds of the formula I described in WO 9827077

in which R is

X is O or S, R¹ is H, Hal, OH, OA, A, alkylene-O-A, NO₂, NH₂, NH-acyl,SO₂NH₂, SO₃-A, SO₂NHA, CN or formyl, R² R³ and R⁴ are each,independently of one another, a phenyl group which is unsubstituted ormonosubstituted or polysubstituted by R⁷, where R is additionally A orcycloalkyl, a

group or a

group, with the proviso that at least one of the radicals R², R³ or R⁴is an R⁸ radical which is unsubstitdted or monosubstituted orpolysubstituted by R⁷, R⁵ is a phenyl group which is unsubstituted ormonosubstituted or polysubstituted by Hal, OH, OA, A, S-A, NO₂, NH₂,NHA, NA₂, NH-acyl, NHSO₂A, NASO₂A, NH(CO)NH₂, NH(CO)NHA, formyl, NHCOOA,NA-acyl, NHCOO-alkylene-OA, NH(CO)NA₂, N-piperidinyl-CO—NH,N-pyrrolidinyl-CONH, O(CH₂)_(n)COOA, O(CH₂)_(n)COOH, O(CH₂)_(n)OH,O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH, COOA, CH₂COOH or CH₂COOA, A is alkylhaving 1-6 carbon atoms, in which one or two CH₂ groups may be replacedby O or S atoms or by —CR⁶═CR⁶— groups and/or 1-7 H atoms may bereplaced by F, D is carbonyl or [C(R⁶R^(6′))]_(m), E is CH₂, S or O, Yis O or S, R⁶ and R^(6′) are each, independently of one another, H, F orA, R⁷ is Hal, OH, OA, O-alkylene-R⁵, A, S-A, S—OA, SO₂A, S—OR⁵, SO₂R⁵,NO₂, NH₂, NHA, NA₂, NH-acyl, NHSO₂A, NHSO₂R⁵, NASO₂A, NASO₂—R⁵,NH(CO)NH₂, NH(CO)NHA, formyl, NH(CO)NHR⁵, NHCOOA, NA-acyl, NHCOOCH₂R⁵,NHSO₂CH₂R⁵, NHCOO-alkylene-OA, NH(CO)NA₂, 1-piperidinyl-CO—NH,1-pyrrolidinyl-CONH, O(CH₂)_(n)COOA, O(CH₂)_(n)COOH, O(CH₂)_(n)OH,O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH, COOA, CH₂COOH or CH₂COOA, R⁸ is a 5-7membered heterocyclic radical having 1-4 N, O and/or S atoms or a

group, G and Z are each, independently of one another, —CH═, N, O or S,L is —CH═, —CH═CH— or —CH₂—CH₂—CH₂—, Hal is fluorine, chlorine, bromineor iodine, n is 0, 1 or 2, and m is 1 or 2, or a tautomeric cyclisedform, and the (E)-isomers and salts of all isomers; m) the compounds ofthe formula I described in WO 9841515

in which X is O or S, R¹ is H, Hal, OH, OA, A, NO₂, NH₂, NHA, NAA′,NHCOR⁴, NHCOR⁶, NHSO₂R⁴, NHSO₂R⁶, S(O)_(m)R⁶, SO₃H, SO₂NR⁴R^(4′) orformyl, R² and R^(2′) are each, independently of one another, A,(CH₂)_(n)Ar, (CH₂)_(n)Het, CH₂COAr, CH₂COHet or OAr, R^(2′) 0 isadditionally also H, R³ is COOR⁴, CN, 1H-tetrazol-5-yl or CONHSO₂R⁵, R⁴and R^(4′) are each, independently of one another, H or A, R⁵ is A orAr, R⁶ is phenyl or naphthyl, each of which is unsubstituted ormonosubstituted, disubstituted or trisubstituted by A, NH₂, NHA, NAA′,NO₂, CN or Hal, R⁷ and R^(7′) are each, independently of one another, Hor alkyl having 1-6 carbon atoms, A and A′ are each, independently ofone another, alkyl having 1-6 carbon atoms, in which one or two CH₂groups may be replaced by O or S atoms or by —CR⁷═CR^(7′) groups and/or1-7 H atoms may be replaced by F, or benzyl, Ar is phenyl or naphthyl,each of which is unsubstituted or monosubstituted, disubstituted ortrisubstituted by A, OR⁴, NH₂, NHA, NAA′, NO₂, CN, Hal, NHCOR⁴, NHCOR⁶,NHSO₂R⁴, NHSO₂R⁶, COOR⁴, OPh, CONH₂, CONHA, CONAA′, COR⁴, CONHSO₂R⁴,CONHSO₂R⁶, O(CH₂)_(n)COOR⁴, O(CH₂)_(n)OR⁴, SO₃H, SO₂NR⁴R^(4′),S(O)_(m)R⁶ or S(O)_(m)R⁴, Het is a monocyclic or bicyclic saturated,unsaturated or aromatic heterocyclic radical having 1-4 N, O and/or Satoms, bonded via N or C, which may be unsubstituted or monosubstituted,disubstituted or trisubstituted by Hal, A, R³, NH₂, NHA, NAA′, NO₂and/or ═O, Hal is fluorine, chlorine, bromine or iodine, m is 0, 1 or 2,and n is 1 or 2, where, if R² is CH₂COAr and R^(2′) is H, R³ is notCOOA, and salts thereof; n) the compounds of the formula I described inWO 9841521

in which Z is a single or double bond, R¹ is a

group which is unsubstituted or monosubstituted in the phenyl moiety byR⁷, or a

group which is unsubstituted or monosubstituted in the cyclohexadienylmoiety by R⁷, R² is A, Ar—(CH₂)_(m), cycloalkyl-(CH₂)_(m), Het-(CH₂)_(m)or R¹—(CH₂)_(m), R³ and R^(3′) are each, independently of one another,OR⁴, NHSO₂R⁵, NH₂, NHA or NAA′, R³ and R^(3′) together are alternatively—O—, forming a cyclic anhydride, R⁴ and R^(4′) are each, independentlyof one another, H or A, R⁵ is A or Ar, R⁶ is phenyl or naphthyl, each ofwhich is unsubstituted or monosubstituted, disubstituted ortrisubstituted by A, NH₂, NHA, NAA′, NO₂, CN or Hal, R⁷ is A, COOR⁴, CN,1H-tetrazol-5-yl, CONHSO₂R⁵, Hal, OR⁴, NO₂, NH₂, NHA, NAA′, NHCOR⁴,NHCOR⁶, NHSO₂R⁴, NHSO₂R⁶, S(O)_(k)R⁴, S(O)_(k)R⁶, SO₂NR⁴R^(4′) orformyl, R⁸ and R^(8′) are each, independently of one another, H or alkylhaving 1-6 carbon atoms, E is CH₂or O, D is carbonyl or (CR⁴R^(4′))_(n),E and D together are alternatively CR⁴═R^(4′), X is S or O, A and A′ areeach, independently of one another, alkyl having 1-6 carbon atoms, inwhich one or two CH₂ groups may be replaced by O or S atoms or by—CR⁸═CR^(8′)— groups and/or 1-7 H atoms may be replaced by F, or benzyl,Ar is phenyl or naphthyl, each of which is unsubstituted ormonosubstituted, disubstituted or trisubstituted by A, OR⁴, NH₂, NHA,NAA′, NO₂, CN, Hal, NHCOR⁴, NHCOR⁶, NHSO₂R⁴, NHSO₂R⁶, COOR⁴, OPh, CONH₂,CONHA, CONAA′, COR⁴, CONHSO₂R⁴, CONHSO₂R⁶, O(CH₂)_(n)COOR⁴,O(CH₂)_(n)OR⁴, SO₂NR⁴R^(4′), S(O)_(k)R⁶ or S(O)_(k)R⁴, Het is amonocyclic or bicyclic saturated, unsaturated or aromatic heterocyclicradical having 1-4 N, O and/or S atoms, bonded via N or C, which may beunsubstituted or monosubstituted, disubstituted or trisubstituted byHal, A, COOR⁴, CN, 1H-tetrazol-5-yl, CONHSO₂R⁵, NH₂, NHA, NAA′, NO₂and/or ═O, Hal is fluorine, chlorine, bromine or iodine, k is 0, 1 or 2,m is 0,1 or 2, and n is 1 or 2, and the (Z)- and (E)-isomers and thesalts of all isomers; o) the compounds of the formula I described in WO9842702

in which R is

X and Y are each, independently of one another, O or S, R¹ is H, Hal,OH, OA, A, alkylene-O-A, NO₂, NH₂, NH-acyl, SO₂NH₂, SO₂-A, SO₂N HA, CNor formyl, R², R³ and R⁴ are each, independently of one another, aphenyl group which is unsubstituted or monosubstituted orpolysubstituted by Hal, OH, OA, O-alkylene-R⁵, A, S-A, S—OA, SO₂A,S—OR⁵, SO₂R, NO₂, NH₂, NHA, NA₂, —NH-acyl, NHSO₂A, NHSO₂R⁵, NASO₂A,NASO₂—R⁵, NH(CO)NH₂, NH(CO)NHA, formyl, NH(CO)NHR⁵, NHCOOA, NA-acyl,NHCOOCH₂R⁵, NHSO₂CH₂R⁵, NHCOO-alkylene-OA, NH(CO)NA₂,1-piperidinyl-CO-NH, 1-pyrrolidinyl-CONH, O(CH₂)_(n)COOA,O(CH₂)_(n)COOH, O(CH₂)_(n)OH, O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH, COOA,CH₂COOH or CH₂COOA, a

group or a

group, where is additionally A or cycloalkyl, R⁵ is a phenyl group whichis unsubstituted or monosubstituted or polysubstituted by Hal, OH, OA,A, S-A, NO₂, NH₂, NHA, NA₂, NH-acyl, NHSO₂A, NASO₂A, NH(CO)NH₂,NH(CO)NHA, formyl, NHCOOA, NA-acyl, NHCOO-alkylene-OA, NH(CO)NA₂,N-piperidinyl-CO—NH, N-pyrrolidinyl-CONH, O(CH₂)_(n)COOA,O(CH₂)_(n)COOH, O(CH₂)_(n)OH, O(CH₂)_(n)OA, CH₂OH, CH₂OA, COOH, COOA,CH₂COOH or CH₂COOA, A is alkyl having 1-6 carbon atoms, in which one ortwo CH₂ groups may be replaced by O or S atoms or by —CR⁶═CR^(6′)—groups and/or 1-7 H atoms may be replaced by F, D is carbonyl or[C(R⁶R^(6′))]_(m), E is CH₂, S or O, R⁶ and R^(6′) are each,independently of one another, H, F or A, R⁷ is —O—C(═Y)—NH—R⁸, R⁸ isalkyl having 1-10 carbon atoms which is unsubstituted or monosubstitutedor disubstituted by R⁹ and in which 1-2 carbon atoms may be replaced byO and/or S and/or may be substituted by ═O, or cycloalkyl, in which 1-2carbon atoms may be replaced by N, O and/or S, R⁹ is phenyl which isunsubstituted or monosubstituted or disubstituted by Hal, naphthyl,A-O—C(═O)— or Hal, Hal is fluorine, chlorine, bromine or iodine, n is 0,1 or 2, and m is 1 or 2, and salts thereof; p) the compounds of theformula I described in WO 9842709

in which X is N—R³, O or S, R is 2,1,3-benzothiadiazol-4-or 5-yl or2,1-benzoisothiazol-5-or 6-yl, each of which is unsubstituted ormonosubstituted or disubstituted by R² and/or R^(2′), or phenyl which isunsubstituted or monosubstituted, disubstituted or trisubstituted by R²and/or R^(2′), R¹ is H or A, R² and R^(2′) are each, independently ofone another, H, A, OH, OA, Hal, OCF₃, OCHF₂, —O—CO-A, —O-alkylene-COOR¹,—O-alkylene-CH₂-OR¹, or OCH₂-phenyl or —O—CO-phenyl, each of which isunsubstituted or monosubstituted or disubstituted in the phenyl moietyby R⁴ and/or R^(4′), R² and R^(2′) together are alternatively —OCH₂O—,—OCH₂CH₂O— or —OCH₂CH₂—, R³ is H, A, alkylene-O-A, —CO—OA, oralkylene-phenyl which is unsubstituted or monosubstituted ordisubstituted in the phenyl moiety by R⁴ and/or R^(4′), R⁴ and R^(4′)are each, independently of one another, H, A, OH, OA, Hal, COOR¹ orCH₂OR¹, A is alkyl having 1-6 carbon atoms, Hal is fluorine, chlorine,bromine or iodine, and salts thereof; q) the compounds of the formula Idescribed in WO 9905132

in which R is

X is O or S, R¹ is H, Hal, OA or A, R², R³, R⁵ and R⁶ are each,independently of one another, H, Hal, A, OA or R⁴, R⁴ is—O—(CH₂)_(n)-Cy, Cy is cycloalkyl having 3-8 carbon atoms, A is alkylhaving 1-6 carbon atoms, in which one or two CH₂ groups may be replacedby O or S atoms or by —CR⁵═CR^(5′)— groups and/or 1-7 H atoms may bereplaced by F, R⁵ and R^(5′) are each, independently of one another, H,F or A, Hal is fluorine, chlorine, bromine or iodine, n is 0, 1 or 2, ora tautomeric cyclised form, and the (E)-isomers and the salts of allisomers, for the preparation of a medicament for inhibiting the growthof neoplastic cells.
 2. Use of endothelin receptor antagonists selectedfrom the group consisting of i) the compounds described in EP 0733626 a)5-bromo-2-ethyl-N-(2,1,3-benzothiadiazol-5-yl)benzenesulfonamide; b)2,5-dichloro-N-(2,1,3-benzothiadiazol-5-yl)benzenesulfonamide; c)5-bromo-2-propyl-N-(2,1,3-benzothiadiazol-5-yl)benzenesulfonamide; d)5-dimethylamino-N-(2,1,3-benzothiadiazol-5-yl)naphthalenesulfonamide; e)5-dimethylamino-N-[6-methyl-(2,1,3-benzothiadiazol-5-yl)]-naphthalenesulfonamide;f)5-dimethylamino-N-[4-bromo-(2,1,3-benzothiadiazol-5-yl)]-naphthalenesulfonamide;g) 5-dimethylamino-N-(2,1,3-benzothiadiazol-4-yl)naphthalenesulfonamide;h)5-dimethylamino-N-([1,2,5]-oxadiazole-[3,4-b]-pyridin-6-yl)-naphthalenesulfonamide;i)5-dimethylamino-N-(1,2,5-benzoxadiazol-5-yl)-1-naphthalenesulfonamide;j)5-dimethylamino-N-(6-bromo-7-methyl-1,2,5-benzoxadiazol-5-yl)-1-naphthalenesulfonamide;k) 2-phenyl-N-(2,1,3-benzothiadiazol-5-yl)benzenesulfonamide; ii) thecompounds described in EP 0758650 a)2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)aceticacid; b)2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)-N-(4-tert-butylphenylsulfonyl)acetamide;c)2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)-N-(4-isopropylphenylsulfonyl)acetamide;d) 2-(1,3-benzodioxol-5-yl)-2-(7-propylquinolin-8-yloxy)acetic acid; e)2-(1,3-benzodioxol-5-yl)-2-(7-propylquinolin-8-yloxy)-N-(4-tert-butylphenylsulfonyl)acetamide;f) 2-(1,3-benzodioxol-5-yl)-2-(6-propylindol-7-yloxy)acetic acid; g)2-(1,3-benzodioxol-5-yl)-2-(1-methyl-2-propylbenzimidazol-4-yloxy)acetic acid; iii) the compounds described in EP 0755934a)1,2-dihydro-1-(2-methoxybenzyl)-4-(4-methoxyphenyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylicacid; b)2-(2-methoxybenzyloxy)-4-(4-methoxyphenyl)benzofuro[3,2-b]-pyridine-3-carboxylicacid; c)4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(2-methoxybenzyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylicacid; d)2-(2-methoxyphenoxy)-4-(4-methoxyphenyl)benzofuro[3,2-b]-pyridine-3-carboxylicacid; e)4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(2-methoxybenzyl)-2-oxo-3-(1H-tetrazol-5-yl)benzofuro[3,2-b]pyridine;f)1,2-dihydro-1-(2,3-methylenedioxybenzyl)-4-(4-methoxyphenyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylicacid; g)1,2-dihydro-1-(2,3-methylenedioxybenzyl)-7-methyl-4-(4-trifluoromethoxyphenyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylicacid; h)1,2-dihydro-1-(2,3-methylenedioxybenzyl)-7-methyl-4-(4-methoxyphenyl)-2-oxobenzothieno[3,2-b]pyridine-3-carboxylicacid; i)1,2-dihydro-1-(2,1,3-benzothiadiazol-5-methyl)-4-(4-methoxyphenyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylicacid; iv) the compounds described in EP 0757039 a)4-(1,3-benzodioxol-5-yl)-1,2-dihydro-1-(2-methoxybenzyl)-2-oxoquinoline-3-carboxylicacid; b)4-(1,3-benzodioxol-5-yl)-1,2-dihydro-1-(4-methoxybenzyl)-2-oxoquinoline-3-carboxylicacid; c)4-(1,3-benzodioxol-5-yl)-1,2-dihydro-1-(3,4-methylenedioxybenzyl)-2-oxoquinoline-3-carboxylicacid; d) 4-(1,3-benzodioxol-5-yl)-1,2-dihydro-1-(2-methoxybenzyl)-2-oxoquinoline-3-acetic acid; e)4-(1,3-benzodioxol-5-yl)-1,2-dihydro-1-(3,4-methylenedioxybenzyl)-2-oxoquinoline-3-aceticacid; f)4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(2-methoxybenzyl)-2-oxoquinoline-3-carboxylicacid; g)4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(4-methoxybenzyl)-2-oxoquinoline-3-carboxylicacid; h)4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(6-chloro-3,4-methylenedioxybenzyl)-2-oxoquinoline-3-carboxylicacid; i)4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(3,4-methylenedioxybenzyl)-2-oxoquinoline-3-carboxylicacid; j)4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(3-methoxybenzyl)-2-oxoquinoline-3-carboxylicacid; v) the compounds described in EP 0796250 a)2-(1,3-benzodioxol-5-yl)-2-(2,3-dihydro-4,6-dimethylpyridazin-3-on-2-yl)-N-(4-isopropylphenylsulfonyl)acetamide;b)2-(1,3-benzodioxol-5-yl)-2-(6-(4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-on-2-yl)-N-(4-isopropylphenylsulfonyl)acetamide;c)2-(1,3-benzodioxol-5-yl)-2-(6-(4-chlorophenyl)-2,3,4,5-tetrahydropyridazin-3-on-2-yl)-N-(4-isopropylphenylsulfonyl)acetamide;d)2-(1,3-benzodioxol-5-yl)-2-(6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-on-2-yl)-N-(4-isopropylphenylsulfonyl)acetamide;e)2-(1,3-benzodioxol-5-yl)-2-(4-methyl-6-phenyl-2,3-dihydro-pyridazin-3-on-2-yl)-N-(4-isopropylphenylsulfonyl)acetamide;f)2-(1,3-benzodioxol-5-yl)-2-(5-(3,4-dimethoxyphenyl)-6-ethyl-2H-3,6-dihydro-1,3,4-thiadiazin-2-on-3-yl)-N-(4-isopropylphenyl-sulfonyl)acetamide;vi) the compounds described in WO9719077 a)3-(1,3-benzodioxol-5-yl)-1-(2,1,3-benzothiadiazol-5-ylmethyl)-5-propoxyindole-2-carboxylicacid; b)3-(4-methoxyphenyl)-1-(2,1,3-benzothiadiazol-5-ylmethyl)-5-ethoxyindole-2-carboxylicacid; c) 3-(4-methoxyphenyl)-1-(2,1,3-benzothiadiazol-5-ylmethyl)-5-propoxyindole-2-carboxylic acid; d)3-(2,1,3-benzothiadiazol-5-yl)-1-(4-methoxybenzyl)-5-ethoxyindole-2-carboxylic acid; e)3-(2,1,3-benzothiadiazol-5-yl)-1-(4-methoxybenzyl)-5-propoxyindole-2-carboxylicacid; f)3-(2,1,3-benzothiadiazol-5-yl)-1-(3,4-methylenedioxybenzyl)-5,6-dimethoxyindole-2-carboxylicacid; vii) the compounds described in WO 97309822-(2,1,3-benzothiadiazol-5-yl)-3-benzyl-4-(4-methoxyphenyl)-4-oxo-2-butenoicacid;2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4,5-trimethoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoicacid;2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4-diisopropoxy-5-methoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoicacid; 2-(2,1,3-benzothiadiazol-5-yl)-3-benzyl-4-(1,4-benzodioxan-6-yl)-4-oxo-2-butenoic acid;2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4,5-trimethoxybenzyl)-4-(1,4-benzodi-oxan-6-yl)-4-oxo-2-butenoicacid;2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4-diisopropoxy-5-methoxybenzyl)-4-(1,4-benzodioxan-6-yl)-4-oxo-2-butenoicacid;2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4,5-trimethoxybenzyl)-4-(1,3-benzodioxol-5-yl)-4-oxo-2-butenoicacid;3-(2,1,3-benzothiadiazol-5-yl)-4-benzyl-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4,5-trimethoxybenzyl)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-butenoicacid;3-(2,1,3-benzothiadiazol-5-yl)-4-[(7-methoxy-1,3-benzodioxol-5-yl)methyl]-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazoi-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-methylthiobenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(3-benzyloxy-4-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(2,3-dihydrobenzofuran-5-ylmethyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(2-methylpropyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-tert-butoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1, 3-benzothiadiazol-5-yl )-4-(4-hydroxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one; 3-(2,1,3-benzothiadiazol-5-yl)-4-(4-trifluoromethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-pentyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-hexyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-phenoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4,5-dimethoxy-3-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,5-dimethoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-chloro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-methyl-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-⁴-(3,⁴-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(2,5-dimethoxyphenyl )-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,3-dihydrobenzofuran-5-yl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-propoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(4-propoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(2,4-dimethoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(4-benzyloxy-2-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(2,3,4-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4, 5-trimethoxybenzyl)-5-hydroxy-5-(2,4-dimethoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-triethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-difluoromethoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(3-hydroxy-4-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(2,4-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(2,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-isopropoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-propoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-6-methyl-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furna-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-benzyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-hydroxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-propoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-isopropoxybenzyl)-5-hydroxy-5-(1,4-benzodioxan-6-yl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-6-methyl-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-hexyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-y)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(1,4-benzodioxan-6-yl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(3-methoxy-5-butoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2-fluoro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-isopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-benzyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-fluoro-2-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-5-ethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-methoxycarbonylbenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybehzyl)-5-hydroxy-5-(4-benzyloxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-4-methyl-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3,-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isobutoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one; 4-(2,1,3-benzothiadiazol-5-ylmethyl)-3-(7-methoxy-1,3-benzodioxol-5-yl)-5-hydroxy-5-(4-methoxyphenyl )-5H-furan-2-one;2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4-diisopropoxy-5-methoxybenzyl)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-butenoic acid;2-(2,1,3-benzothiadiazol(-5-yl)-3-(3,5-dimethoxy-4-isopropoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic acid;2-(2,1,3-benzothiadiazol-5-y)-3-(3,4-dimethoxy-5-isopropoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic acid;2-(2,1,3-benzothiadiazol-5-yl)-3-(3,5-dimethoxy-4-isopropoxybenzyl)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-butenoic acid;2-(2,1,3-benzothiadiazol-5-yl)-3-(3,4,5-trimethoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoicacid; viii) the compounds described in WO 9730996 a)3-(2,1,3-benzothiadiazol-5-aminosulfonyl)-N-(6-methyl-1,3-benzodioxol-5-yl)thiophene-2-carboxamide;b)3-(2,1,3-benzothiadiazol-5-aminosulfonyl)-N-(6-acetyl-1,3-benzodioxol-5-yl)thiophene-2-carboxamide;c)3-(2,1,3-benzothiadiazol-5-aminosulfonyl)-N-(6-cyano-1,3-benzodioxol-5-yl)thiophene-2-carboxamide;d)3-(2,1,3-benzothiadiazol-5-aminosulfonyl)-2-(6-methyl-1,3-benzodioxol-5-ylmethylcarbonyl)thiophene;ix) the compounds described in DE 19609597 a)N-(2,1,3-benzothiadiazol-5-yl)-5-N′-isopropylamino-1-naphthalenesulfon-amide;b)N-(2,1,3-benzothiadiazol-5-yl)-5-N′-propylamino-1-naphthalenesulfon-amide;c)N-(2,1,3-benzothiadiazol-5-yl)-5-N′-methylamino-1-naphthalenesulfon-amide;d)N-(2,1,3-benzothiadiazol-5-yl)-5-N′-ethylamino-1-naphthalenesulfon-amide;e)N-(2,1,3-benzothiadiazol-5-yl)-5-N′-butylamino-1-naphthalenesulfon-amide;x) the compounds described in DE 19612101 a)4-(4-methoxyphenyl)-1,6-dihydro-1-(2-methoxybenzyl)-2-methyl-6-oxopyrimidine-5-carboxylicacid; b)4-(3,4-methylenedioxyphenyl)-1,6-dihydro-1-(2-methoxybenzyl)-2-cyclopropyl-6-oxopyrimidine-5-carboxylicacid;c)4-(2-carboxy-4-methoxy-7-benzofuranyl)-1,6-dihydro-1-(2-methoxybenzyl)-2-methyl-6-oxopyrimidine-5-carboxylicacid;d)4-(2-phenyl-4-methoxyphenyl)-1,6-dihydro-1-(2-methoxybenzyl)-2-methyl-6-oxopyrimidine-5-carboxylicacid; e)4-(2-carboxy-4-methoxy-7-benzofuranyl)-1,6-dihydro-1-(5-benzothiadiazolyl)-2-methyl-6-oxopyrimidine-5-carboxylicacid; f)4-(4-methoxyphenyl)-1,6-dihydro-1-(5-benzothiadiazolyl)-2-methyl-6-oxopyrimidine-5-carboxylicacid; xi) the compounds described in WO 9827091 a)4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-benzyl-3-butyl-1H-pyrazole-5-carboxylicacid; b) 4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-methoxybenzyl)-3-butyl-1H-pyrazole-5-carboxylic acid; c)4-(2,1,3-benzothiadiazol-6-chloro-5-ylmethyl)-1-(3-methoxybenzyl)-3-butyl-1H-pyrazole-5-carboxylic acid; d)4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(2-carboxymethoxy-4-methoxybenzyl)-3-butyl-1H-pyrazole-5-carboxylicacid; e)4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(2,4-dimethoxybenzyl)-3-butyl-1H-pyrazole-5-carboxylicacid; f)4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-methoxybenzyl)-3-phenyl-1H-pyrazole-5-carboxylicacid; g)4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-methoxybenzyl)-3-(2-thienyl)-1H-pyrazole-5-carboxylicacid; h)4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-methoxybenzyl)-3-cyclohexyl-1H-pyrazole-5-carboxylicacid; i) 4-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(2-carboxymethoxy-4-methoxybenzyl)-3-propoxy-1H-pyrazole-5-carboxylicacid; xii) the compounds described in WO 9827077 a)2-(2,1,3-benzothiadiazol-5-yl )-3-(thien-2-ylmethyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic acid; b)2-(2,1,3-benzothiadiazoi-5-yl)-3-(5-methoxythien-2-ylmethyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoicacid; c) 3-(2,1,3-benzothiadiazol-5-yl )-4-(furan-2-yl methyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one; d)3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-5H-furan-2-one;e)3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-5H-furan-2-one;f)3-(2,1,3-benzothiadiazol-5-yl)-4-(thien-3-ylmethyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;xiii) the compounds described in WO 9841515 a)2-(2,1,3-benzothiadiazol-5-yl)-4-(4-methoxyphenyl)-4-oxo-2-butanoicacid; b)2-(2,1,3-benzothiadiazol-5-yl)-3-(2,1,3-benzothiadiazol-5-ylmethyl)aceticacid; c)2-(2,1,3-benzothiadiazol-5-yl)-2-(4-methoxycarbonylbenzyl)acetic acid;d) 2-(2,1,3-benzothiadiazol-5-yl)-2-(4-methoxycarbonylbenzyl)-N-(4-isopropylphenylsulfonyl)acetamide; e)2-(2,1,3-benzothiadiazol-5-yl)-2-(4-carboxybenzyl)-N-(4-isopropylphenylsulfonyl)acetamide;f) 2-(2,1,3-benzothiadiazol-5-yl )-4-(4-methoxybenzyl )acetic acid; g)2-(2,1,3-benzothiadiazol-5-yl )-2-(4-methoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butanoic acid; xiv) the compoundsdescribed in WO 9841521 a)2-(1,3-benzodioxol-5-yl)-3-(2,1,3-benzothiadiazol-5-yl)succinic acid; b)2,3-bis(1,3-benzodioxol-5-yl)maleic acid; c)N,N-dibutyl-2,3-bis(1,3-benzodioxol-5-yl)maleamide; d)2,3-bis(1,3-benzodioxol-5-yl)maleic anhydride; e)2-(1,3-benzodioxol-5-yl)-3-phenylmaleic anhydride; xv) the compoundsdescribed in WO 9842702 ethyl [3-(2,1, 3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-(4-methoxyphenyl)-5H-furan-2-on-5-yloxycarbonylamino]acetate; ethyl[3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-on-5-yloxycarbonylamino]acetate;N-1-naphthylethyl-[3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-on-5-yl]carbamate;ethyl2-[3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-on-5-yloxycarbonylamino]-3-methylbutyrate;2-(2,1,3-benzothiadiazol-5-yl)-3-(3-fluoro-4-methoxybenzoyl)-4-(3,4,5-trimethoxyphenyl)but-2-enoicacid;3-(2,1,3-benzothiadiazol-5-yl)-4-benzyl-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1, 3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-[(7-methoxy-1,3-benzodioxol-5-yl)methyl]-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-methylthiobenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3-benzyloxy-4-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(2,3-dihydrobenzofuran-5-ylmethyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(2-methylpropyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-d imethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(4-tert-butoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-hydroxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-trifluoromethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-pentyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(3,5-dimethoxy-4-hexyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-phenoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4,5-dimethoxy-3-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,5-dimethoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-chloro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-methyl-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(2,5-dimethoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,3-dihydrobenzofuran-5-yl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-propoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(4-propoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxy-5-methoxybenzyl)-5-hydroxy-5-(2,4-dimethoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-⁵-yl)-4-(4-benzyloxy-2-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one; 3-(2,1,3-benzothiadiazol-5-yl)-4-(2,3,4-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2,4-dimethoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(3,4,5-triethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-difluoromethoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(3-hydroxy-4-methoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl )-4-(2,4-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(2,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-isopropoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-propoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-6-methyl-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-benzyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-hydroxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-propoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadian)-5-yl)-4-(3,4-dimethoxy-5-isopropoxybenzyl)-5-hydroxy-5-(1,4-benzodioxan-6-yl)-5H-furna-2-one;3-(2,1,3-benzothiadiazol-6-methyl-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-isopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-hexyloxybenzyl)-5-hydroy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isopropoxybenzyl)-5-hydroxy-5-(1,4-benzodioxan-6-yl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3-methoxy-5-butbxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(2-fluoro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-isopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-dimethoxy-5-benzyloxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-fluoro-2-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-y)-4-(3,5-dimethoxy-5-ethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(4-methoxycarbonylbenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4-diisopropoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-benzyloxyphenyl)-5H-furna-2-one;3-(2,1,3-benzothiadiazol-4-methyl-5-yl)-4-(3,4,5-trimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;3-(2,1,3-benzothiadiazol-5-yl)-4-(3,5-dimethoxy-4-isobutoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;4-(2,1,3-benzothiadiazol-5-yl)-3-(7-methoxy-1,3-benzodioxol-5-yl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;and the open-chain tautomers; xvi) the compounds described in WO 9842709a)3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(4-methoxyphenyl)-8-methyl-3,8-dihydro-3,8-diazacyclopenta[a)indene-2-carboxylicacid; b)3-(2-methoxybenzyl)-1-(4-methoxyphenyl)-8-methyl-3,8-dihydro-3,8-diazacyclopenta[a]indene-2-carboxylicacid; c)3-(2,5-dimethoxybenzyl)-1-(4-methoxyphenyl)-8-methyl-3,8-dihydro-3,8-diazacyclopenta[a]indene-2-carboxylicacid;d)3-(1,3-benzodioxol-5-ylmethyl)-1-(4-methoxyphenyl)-8-methyl-3,8-dihydro-3,8-diazacyclopenta[a]indene-2-carboxylicacid; e)3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(4-methoxyphenyl)-8-oxa-3-azacyclopenta[a]indene-2-carboxylicacid; f)3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(4-methoxyphenyl)-8-thia-3-azacyclopenta[a]indene-2-carboxylicacid; g)3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-carboxymethoxy-4-methoxyphenyl)-8-methyl-3,8-dihydro-3,8-diazacyclopenta[a]indene-2-carboxylicacid; h) 3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-carboxymethoxy-4-methoxyphenyl)-8-oxa-3-azacyclopenta[a]indene-2-carboxylicacid;i)3-(2,1,3-benzothiadiazol-5-ylmethyl)-1-(3-carboxymethoxy-4-methoxyphenyl)-8-thia-3-azacyclopenta[a]indene-2-carboxylicacid; xvii) the compounds described in WO 9905132 a)2-(2,1,3-benzothiadiazol-5-yl)-3-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoic acid; b) 2-(2,1,3-benzothiadiazol-5-yl)-3-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-butenoic acid; c)3-(2,1,3-benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one;d)3-(2,1,3-benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one; e)3-(2,1,3-benzothiadiazol-5-yl )-4-(3-cyclopentyloxy-4,5-dimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one; f)3-(7-methyl-2,1,3-benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-5-hydroxy-5-(3-fluoro-4-methoxyphenyl)-5H-furan-2-one;and physiologically acceptable salts and/or solvates thereof for thepreparation of a medicament for inhibiting the growth of neoplasticcells.
 3. Use of endothelin receptor antagonists selected from the groupconsisting of a)5-dimethylamino-N-(2,1,3-benzothiadiazol-5-yl)naphthalenesulfonamide; b)2-(2,1,3-benzothiadiazol-5-yl)-3-(3-fluoro-4-methoxybenzoyl)-4-(3,4,5-trimethoxyphenyl)but-2-enoicacid; and physiologically acceptable salts and/or solvates thereof forthe preparation of a medicament for inhibiting the growth of neoplasticcells.
 4. Use of endothelin receptor antagonists as defined in claim 1for the preparation of a medicament for the treatment and/or prophylaxisof cancer diseases.
 5. Use of endothelin receptor antagonists as definedin claim 1 for the preparation of a medicament for the treatment ofprecancerogenic damage.
 6. Use of endothelin receptor antagonists asdefined in claim 1 for the preparation of a medicament for regulatingapoptosis in human cells.
 7. Use according to claim 4, where the cancerdiseases are selected from the group consisting of prostate cancer,ovarian carcinoma, intestinal cancer, cervical carcinoma, melanoma andpancreatic cancer.